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Reevaluating the WHI Findings
Beginning several years ago, on our own sister site,
Breast
Cancer Watch, we have ourselves challenged the methodology
underlying one of the major seminal studies that butressed
the WHI findings, especially outside of the US, namely
the British Million Women Study (see below for our extensive
critique of the British MWS), concluding that it failed
to support its conclusion of the association of HRT
and risk of breast cancer. More recently, beginning
as far back as 2002 with Paul McDonough at the Medical
College of Georgia (Fert Steril (2002): The
randomized world is not without its imperfections: reflections
on the Women's Health Initiative Study).
This was followed by the critique by two Schering AG
researchers Machen & Schmidt-Gollwitzer (Hum Reprod
(2003):
Issues to debate on the Women’s Health Initiative
(WHI) study. Hormone replacement therapy: an epidemiological
dilemma?) who correctly drew attention to the
atypical population studied by WHI: (1) the majority
of participants were elderly postmenopausal women who
had gone through menopause approx. 10 years before (mean
patient age was 63), and (2) who also had a negative
history of acute cardiovascular events (36% of these
postmenopausal women were on antihypertensive drugs,
20% were administered aspirin, and 7% were on statins),
whereas in the general population, HRT is usually started
in menopausal women who are much younger and presumably
healthier.
At about the same time, Samuel Shapiro at the Mailman
School of Public Health, Columbia University, showed
(Shapiro, Climacteric (2003): Risks
of estrogen plus progestin therapy: a sensitivity analysis
of findings in the Women's Health Initiative randomized
controlled trial) that the WHI findings on the
HRT/BC risk association could have been accounted for
by bias, noting correctly that for differences in incidence
of the order of 0.7-0.8/1000 per year as found, it is
not possible to discriminate between causation and detection
bias as alternative explanations for the findings.
And Edward Klaiber and colleagues at the University
of Massachusetts Medical Center concluded in their own
critique of the WHI study (Klaiber et al., Fertil Steril
(2005): A
critique of the Women’s Health Initiative hormone
therapy study) that its major design flaws led
to invalid adverse conclusions about the positive effects
of hormone therapy.
In addition, Portuguese researcher Manuel Neves-e-Castro
pointed out (Hum Reprod (2003): Menopause
in crisis post-Women’s Health Initiative? A view
based on personal clinical experience) that
even if the WHI findings were to be considered motivated,
nonetheless on that basis it is possible to define the
profile for a woman to ‘safely’ initiate HRT:
(1) is between 50 and 59 years of age, (2) with vasomotor
symptoms, (3) <10 years after the menopause, and
(4) being treated with statins or otherwise with a good
lipid profile and a body mass index >30 (for breast
cancer protection), and that indeed this is precisely
the profile of the great majority of women who seek
HRT after their menopause.
More recently, Samuel Shapiro (see above) and two German
researchers, M. Deitel and M.A. Lewis (Deitel et al.,
Hum Reprod (2005): Hormone
replacement therapy: pathobiological aspects of hormone-sensitive
cancers in women relevant to epidemiological studies
on HRT: a mini-review), summarized the demonstrations
of several researchers suggesting that the WHI trial
fails to even qualify as a randomized placebo-controlled
study, and hence cannot claim the rigor and methodological
status of an RCT, since (1) after randomization, women
were free to decide whether to continue their assigned
treatment or undergo diagnostic procedures, (2) almost
half of the women in the combined estrogen + progestin
group were aware of their treatment (the rate of unblinding
in the E+P group was 45%), and (3) participants received
several warnings about the detection of increased risks
of myocardial infarction, stroke and pulmonary embolism
during the study, methodological flaws severe even to
render the WHI study no better than any standard observational
study with all of such studies known associated limitations.
Breast
Cancer Watch
further notes that the association between HRT and increased
breast cancer risk is indirectly under assault and challenge
in other subtle ways. So for example, Per Hall at the
Karolinska Institutet in Sweden and coresearchers have
recently shown (Hall et al., BMC Med (2006): Hormone-replacement
therapy influences gene expression profiles and is associated
with breast-cancer prognosis: a cohort study)
that a gene expression profile (based on 276 genes)
in ER-positive HRT users is significantly associated
with better survival, in terms of longer RFS (recurrence-free
survival), and that HRT use appears to alter only the
expression profiles of ER-positive breast cancers; as
they further observe, paradoxically, although HRT is
considered an ER agonist, the expression profile induced
after prolonged HRT use was opposite to that of estradiol,
and consistent with the effects of tamoxifen in MCF-7
breast cancer cells. Finally, the authors speculate
that given that the favorable survival in HRT users
seemed to be confined to those treated with tamoxifen,
there may be similarities in gene expression between
HRT-exposed tumors and tamoxifen-treated breast cancer
cells. This and similar findings have led some observers
such as Kenny Kwan and associates at King's College
Hospital to conclude that "HRT may be safe in
women with receptor-negative disease or receptor-positive
cancers in the presence of tamoxifen" (Kwan
et al., J Br Menopause Soc (2005): Is
there a role for hormone replacement therapy after breast
cancer?).
Most recently, James Clark of the Department of Molecular
and Cellular Biology at Baylor College of Medicine has
delivered an extensive and closely reasoned critique
of the WHI statistical data analysis and putatively
derived conclusions thereof (J. Clark, Nucl Recept Signal
(2006): A
critique of Women’s Health Initiative Studies (2002-2006)),
concluding that the only valid and supported conclusions
of the WHI E+P study are that for such HRT use, there
is no significant risk for invasive breast cancer, nor
for cardiovascular disease, stroke and venous thromboembolism,
and that given this "it is likely that an untold
number of women will suffer from diseases which post-menopausal
hormone treatment could have prevented".
- Treatment
of Menopause-associated Vasomotor Symptoms:
The North American Menopause Society (NAMS) has conducted
and published in 2004 (Menopause: Treatment
of menopause-associated vasomotor symptoms: position
statement of The North American Menopause Society
[pdf]) an evidence-based review of the treatment of
menopausal vasomotor symptoms, especially hot flashes,
and this represents one of the most comprehensive and
authoritative assessments of this issue to date. Many
of these assessments are independently confirmed in
the more recent systematic literature review of Fugate
& Church (Ann Pharmacother (Sept. 2004):
Nonestrogen
Treatment Modalities for Vasomotor Symptoms Associated
with Menopause) where it was found that black
cohosh, gabapentin, medroxyprogesterone acetate, SSRIs
(i.e., paroxetine hydrochloride), and soy protein have
been shown to be safe and effective in short-term use
as postmenopausal vasomotor treatments. In
addition, much of these conclusions are in agreement
with the findings presented in a recent NIH Consensus
Statement (Ann Intern Med (2005): National
Institutes of Health State-of-the-Science Conference
Statement: Management of Menopause-Related Symptoms).
We present below the NAMS and largely congruent findings
of Fugate and Church, and of the NIH Consensus Statement,
although as we will note directly below, Breast Cancer
Watch disagrees with certain of the these recommendations,
and so we either present our divergent commentary inline
at the appropriate point of discussion, or below in
a separate discussion when the extensiveness of commentary
warrants expanded discussion.
Finally, we note that there is some evidence that HRT
may be still be safe in (1) women with receptor-negative
breast cancer disease or (2) receptor-positive cancers
in the presence of tamoxifen-induced estrogen deprivation
(Kwan et al., J Br Menopause Soc (2005):
Is there a role for hormone replacement therapy after
breast cancer?).
- Lifestyle-related
strategies:
Keeping the core body temperature cool, regular exercise,
maintaining healthy BMI, smoking cessation, relaxation,
in particular in the form of paced respiration, avoidance
of thermally hot and/or spicy foods, were somewhat effective
without reported adverse effects, although Breast Cancer
Watch speculates that in these contexts it may be safe
regrettably because it is render ineffective by virtue
of its estrogenic activity being overwhelmed by the
estrogen-deprivation state, especially in the case of
tamoxifen.
Breast Cancer Watch
Commentary: Exercise:
We find the evidence regarding the impact of exercise
on menopausal vasomotor symptoms more equivocal than
suggested in the NAMS recommendations. The Swedish observational
study of Li et al., Am J Obstet Gynecol (2003): Menopause-related
symptoms: What are the background factors? A prospective
population-based cohort study of Swedish women (The
Women's Health in Lund Area study) noted a relationship
with relatively vigorous physical activity and reduced
hot flashes. On the other hand, Aiello et al. (Menopause
(2004): Effect
of a yearlong, moderate-intensity exercise intervention
on the occurrence and severity of menopause symptoms
in postmenopausal women) found that exercise
does not seem to decrease the risk of having menopause
symptoms in overweight, postmenopausal women not taking
hormone therapy, and may indeed increase the severity
of some symptoms. All
told, our Breast Cancer Watch review of the remaining
literature failed to discover any truly determinative
results, and so the debate on whether exercise materially
and beneficially influences hot flashes will only be
resolved with further sufficiently powered studies.
- Isoflavones:
Some class of women derive significant benefit from
soy products in amounts of 40 mg to 80 mg per day. These
are equol producers: equol is a nonsteroidal estrogen
of the isoflavone class, and it has been found that
some people (equol producers) were more prone to create
the molecule from soy than others, and equol producers
appear to be beneficiaries of the positive effects of
soy on vasomotor symptoms.
Note however that NAMS did not find benefit in other
isoflavone products: red clover (in products like Rimostil
or Promenstil). Finally, additional studies are required
to differentiate the effects of isoflavones from whole
food, soy protein and soy extracts.
Breast Cancer Watch Commentary:
Isoflavones:
(1) Some clarification of the potential benefit of isoflavones
on menopausal vasomotor symptoms has occurred in several
recent well-designed studies. The RCT of Russo &
Coroso (Acta Biomed Ateneo Parmense (2003): The
clinical use of a preparation based on phyto-oestrogens
in the treatment of menopausal disorders) examined
the efficacy of soya isoflavones, finding an associated
significant reduction in some of the disorders linked
with the menopause, especially hot flushes. Similarly,
Nahas et al. (Maturitas (2004): Benefits
of soy germ isoflavones in postmenopausal women with
contraindication for conventional hormone replacement
therapy) found that soy germ isoflavone exerted
favorable effects on vasomotor symptoms as well as lipid
profile, with no change in vaginal cytology, and hence
may be deployed as alternative therapy for the postmenopausal
women with contraindication for conventional HRT. Finally,
in another RCT, Crisafulli et al. (Menopause (2004):
Effects
of genistein on hot flushes in early postmenopausal
women: a randomized, double-blind EPT- and placebo-controlled
study) evaluated and compared the effects of
the phytoestrogen genistein (54 mg/day) to estrogen-progestogen
therapy (EPT) on hot flushes and endometrial thickness
in postmenopausal women, concluding that genistein exhibits
positive effects on hot flushes without a negative impact
on endometrial thickness, and hence may be a strategically
therapeutic alternative in the management of postmenopausal
symptoms. However,
a recent systematic review of this issue by Krebs et
al. (Obstet Gynecol (2004): Phytoestrogens
for treatment of menopausal symptoms: a systematic review)
concluded that phytoestrogens available as soy foods,
soy extracts, and red clover extracts do not improve
hot flushes or other menopausal symptoms. Hence, given
conflicting findings coupled with the ssue of standardization
and variations in active constituents and preparations,
the debate is likely to continue.
(2) Breast Cancer Watch
however finds the evidence for a positive effect of
isoflavones on bone health not conclusive to date. Whereas
the double-blind study of Gallagher et al. (Menopause
(2004): The
effect of soy protein isolate on bone metabolism)
did not find a significant positive effect of soy protein
isolate supplemented with varying amounts of isoflavones
on BMD or on the serum lipid profile in early postmenopausal
women, Atkinson et al. (Am J Clin Nutr (2004): The
effects of phytoestrogen isoflavones on bone density
in women: a double-blind, randomized, placebo-controlled
trial) did find that loss of lumbar spine bone
mineral content and bone mineral density was significantly
lower in the women taking the isoflavone supplement,
red clover (Promensil) than in those taking the placebo,
and although there were no significant treatment effects
on hip bone mineral content or bone mineral density,
markers of bone resorption, or body composition, yet
bone formation markers were significantly increased
in the intervention group compared with placebo in postmenopausal
women, suggesting that isoflavones have a potentially
protective effect on the lumbar spine in women through
attenuation of bone loss. In addition, Chen et al. writing
in the same journal as that of the Gallagher study (Menopause
(2004) : Beneficial
effect of soy isoflavones on bone mineral content was
modified by years since menopause, body weight, and
calcium intake: a double-blind, randomized, controlled
trial) found a modulated beneficial effect on
bone mineral content (BMC). However this study may suggest
an explanation for the perceived divergence of results:
they found that the independent effect of soy on the
maintenance of hip BMC is more marked in women in later
menopause and in those with lower BW (body weight) or
calcium intake, so that the partially determinative
factors may be years since menopause (YSM), body weight
(BW), and dietary calcium intake for postmenopausal
women, factors not explicitly controlled in other studies.
(3) Breast Cancer Watch disagrees with the NAMS
categorical statement as to the lack of efficacy of
red clover isoflavones on menopausal vasomotor symptoms:
the NAMS position is largely founded on the well-publicized
results of the so-called ICE study (Tice et al., JAMA
(2003): Phytoestrogen
Supplements for the Treatment of Hot Flashes: The Isoflavone
Clover Extract (ICE) Study - A Randomized Controlled
Trial). But these results are in conflict with
several other studies finding a significant beneficial
effect of red clover extract on hot flashes, including
the well-designed randomized, double blind, placebo-controlled
trial of van de Weijer and Barentsen (Maturitas (2002):
Isoflavones
from red clover (Promensil®) significantly reduce
menopausal hot flush symptoms compared with placebo),
the randomized double-blind prospective study of Jeri
(The Female Patient (2002): The
Use of an Isoflavone Supplement to Relieve Hot Flushes),
and the findings reported by Woods and Whitehead (Annual
Meeting of the British Menopause Society (Manchester,
July 2003): Effects of red clover isoflavones (Promensil)
versus placebo on uterine endometrium, vaginal maturation
index and the uterine artery in healthy postmenopausal
women). In addition, we agree with the observation
made by Prof. Alan Husband that the ICE study may have
been confounded by an atypically large and unexplained
36% placebo effect (compared with 15 - 20% experienced
by most other studies evaluating isoflavones for menopausal
hot flush management). See also the review of Barentsen
(J Br Menopause Soc (2004): Red
clover isoflavones and menopausal health) who
despite methodological issues concludes that "the
conflicting data are encouraging" and that the
ICE study should not be seen as wholly determinative.
We await further sufficiently powered studies to resolve
the issue.
A recent study weighs in on the side of isoflavone's
efficacy: Lukaczer et al. (Altern Ther Health Med (2005):
Clinical
effects of a proprietary combination isoflavone nutritional
supplement in menopausal women: a pilot trial)
evaluated a nutritional supplement containing isoflavones
from kudzu and red clover, along with other targeted
nutrients, on menopausal symptoms and markers of breast
cancer and CVD risk, finding that this combination isoflavone
nutritional supplement may significantly relieve the
most troubling symptoms of menopause, severe hot flushes
and night sweats, providing a 46% decrease in reported
hot flushes, from an average of 9.7 to 5.2 per day.
Notably, it also confered some chemopreventive and cardioprotective
benefits: it was both the case that two markers of CVD
risk, the ratio of total cholesterol to high-density
lipoprotein (HDL) cholesterol and homocysteine, showed
modest improvement, and that a proposed marker of breast
cancer risk, the ratio of 2-hydroxyestrone to 16 alpha-hydroxyestrone,
also showed a statistically significant improvement.
[Soy Supercomplex + from Rainbow Light in the USA, and
Avlimal from Berkeley Premium Nutraceuticals in the
UK, are both standardized nonprescription isoflavone
preparations derived from kudzu and red clover].
- Vitamin
E:
Findings were inconclusive, but given its nontoxicity
at low doses, it may be considered a reasonable option
to try; effects, if any, may require several weeks to
appear.
- OTC
Progesterone Creams:
NAMS notes that nonprescription wild yam extract and
other commercial topical so-called progesterone products
appear to contain only progesterone precursors (with
some occasional adulteration with progesterone), not
active progestins, and NAMS recommends against their
use.
- Other
Nonprescription Therapies:
NAMS assessed the findings to be inconclusive or not
available for dong quai, evening primrose oil, ginseng,
licorice, Chinese herb mixtures (or TCM: Traditional
Chinese medicine), acupuncture, or magnetic therapy,
and NAMS recommends against their deployment.
Breast Cancer Watch Commentary:
Wyon et al. (Climacteric (2004): A
comparison of acupuncture and oral estradiol treatment
of vasomotor symptoms in postmenopausal women)
compared the effects of electro-acupuncture with oral
estradiol and superficial needle insertion on hot flushes
in postmenopausal women; although finding that electro-acupuncture
decreased the number of flush significantly (~ 50%,
as compared with estrogen at 90%), Breast Cancer Watch
notes that so did the placebo procedure of superficial
needle insertion, allowing for the possibility of an
acupuncture placebo effect.
- Hormonal
Therapies:
NAMS recommends considering lower than standard doses
of ET (estrogen(-only) therapy) and EPT (estrogen-progestin
therapy):
conjugated estrogen tablet at daily
doses of 0.3 mg
17ß-estradiol tablet at 0.25-0.5 mg,
or
17ß-estradiol patch at 0.025 mg.
Transition from oral contraceptives (OC) to ET or EPT
should be accomplished as soon as appropriate to minimize
hormone exposure, as OCs contain more potent hormones
even at their low dosages.
NAMS recommends using continuous regimens before cyclic
regimens for hot flashes.
NAMS duly notes the findings of the Women's Health Initiative
(WHI) and HERS (Heart and Estrogen/Progestin Study)
associating hormone therapy and increased risk of breast
cancer in older women, as well as increased risk of
thromboembolism, Alzheimer's disease and CAD (coronary
artery disease).
Breast Cancer Watch Warning
on Low Dose Hormone Therapy:
We disagree strongly with the NAMS recommendation to
consider the use of lower than standard doses of hormone
therapy: the implication that serious adverse effects
associated with traditional doses of estrogens may be
averted by deployment of such low-dose estrogen preparations
is without evidential foundation in the literature.
Thus, in a recent and comprehensive review, Crandall
(Medscape: Low-Dose
Estrogen Therapy for Menopausal Women: A Review of Efficacy
and Safety) found that evidence as to the long-term
safety and efficacy of low dose preparations is not
reassuring, with no data to suggest that the incidence
of breast cancer and cardiovascular risk is any lower
than with traditional doses of estrogens, concluding
that "clearly, the low-dose preparations should
not be emphasized as being safer than the traditional
(e.g., CEE 0.625 mg/day) estrogen doses". Indeed,
any assurance may be more than illusory, as it was found
that several low-dose preparations failed to protect
significantly against bone loss (especially femoral
neck).
Low-dose Estradiol Vagifem Tablet Contraindicated
Furthermore, there is evidence that even topical vaginal
estrogen preparations - like like the widely used vaginal
estradiol tablet Vagifem - are incorrectly perceived
to result in minimal systemic absorption of estrogen,
but in fact Vagifem significantly raised systemic estradiol
levels over a 12 week term (rising in the 2 weeks following
commencement of Vagifem, usually with a decrease after
1 month of therapy but with not in general with a return
to pre-Vagifem levels) in women under aromatase inhibito
(AI) breast cancer therapy (Kendall et al., Ann Oncol
(2006): Caution:
Vaginal estradiol appears to be contraindicated in postmenopausal
women on adjuvant aromatase inhibitors), reversing
the estradiol suppression achieved by the AI , and so
should be strictly contraindicated in the breast carcimoma
setting.
- Progestin
Therapies:
Progestin and Progesterone
Although both oral and intramuscular progestin and progesterone
have been shown to benefit hot flashes, NAMS notes that
a limiting factor is the major adverse effect of uterine
bleeding, in essential agreement with another review
(Haimov-Kochman & Hochner-Celnikier, Acta Obstet
Gynecol Scand (2005): Hot
flashes revisited: pharmacological and herbal options
for hot flashes management. What does the evidence tell
us?). Furthermore, NAMS found the evidence inconclusive
as to any association of depot-medroxyprogesterone with
bone loss.
Megestrol acetate (Megace)
NAMS found that this oral progestin may be of benefit
after 3 to 4 weeks,when taken at low doses (20 mg twice
daily).
NAMS found clinical trial data are lacking for androgen-estrogen
therapy, noting the concerns about long-term use of
androgens.
- Antidepressants:
For women who are not candidates for estrogen therapy,
including breast cancer survivors, NAMS recommends the
antidepressants venlafaxine (37.5-75.0 mg/day), paroxetine
(12.5-25.0 mg/day), or fluoxetine (20.0 mg/day); onset
of benefit appears t be relatively rapid (within 1 to
2 weeks). NAMS advises initiating treatment with very
low doses, with increases if necessary over weeks, and
cessation under gradual tapering. This is partially
confirmed (Biglia et al., Maturitas (2005): Evaluation
of low-dose venlafaxine hydrochloride for the therapy
of hot flushes in breast cancer survivors) for
low dose (37.5 mg/day) venlafaxine as an effective treatment
for the relief of vasomotor symptoms in patients previously
treated for breast cancer, as well as in those patients
using tamoxifen as adjuvant therapy, with minimal side
effects. Note that improvement in hot flushes may require
over 8 weeks of use.
There have recently been several pilot studies examining
the role of other antidepressants on menopausal symptoms:
Barton et al. (J Support Oncol (2003): Pilot
evaluation of citalopram for the relief of hot flashes)
found that citalopram (Celexa), during the first week
of treatment at 10 mg/day, with 20 mg/day for the following
three weeks, significantly reduced hot flashes, with
additional benefits of decreased anger, tension and
depression, as well as improved mood; and Perez et al.
(J Support Oncol (2004): Pilot
evaluation of mirtazapine for the treatment of hot flashes)
found that mirtazapine (Remeron) at a dose of 7.5 mg
at bedtime, increased to 15 mg at week 3, 30 mg at week
4, and either 15 mg or 30 mg at week 5 by patient choice,
provided significant relief from hot flashes, with only
increases in appetite and dry mouth as typical side
effects.
Breast Cancer Watch Commentary
on Antidepressants:
The NAMS findings as to the modest efficacy (mean reduction,
50-67%, less than that observed with estrogen therapy
(90%)) of antidepressants - in particular, Effexor (Venlafaxine),
Prozac (Fluoxetine), and Paxil (Paroxetine) - are cross-supported
in the literature: see Koch (Ann Pharmacother (2004):
Selective
Serotonin-Reuptake Inhibitors for the Treatment of Hot
Flashes) and Hackley et al. (Medscape Review:
J Midwifery Womens Health : Managing
Menopausal Symptoms After the Women's Health Initiative).
(1) On the extremes, we note that Breast Cancer Watch
finds least compelling the results on fluoxetine and
citalopram (see the Suvanto-Luukkonen et al. Menopause
(2005): Citalopram
and fluoxetine in the treatment of postmenopausal symptoms:
a prospective, randomized, 9-month, placebo-controlled,
double-blind study, which found that citalopram
and fluoxetine have little effect on hot flushes); most
compelling are the results on paroxetine and venlafaxine
(Evans et al., Obstet Gynecol (2005): Management
of Postmenopausal Hot Flushes With Venlafaxine Hydrochloride:
A Randomized, Controlled Trial) with other agents
such as sertaline (Zoloft) not appearing significantly
more effective than placebo in this regard. A recent
RCT (Stearns et al., J Clin Oncol (2005): Paroxetine
Is an Effective Treatment for Hot Flashes: Results From
a Prospective Randomized Clinical Trial) reconfirmed
earlier findings as to the efficacy of paroxetine in
the treatment of hot flashes in women with or without
prior breast cancer, noting that although efficacy was
similar between two tested doses (10mg and 20mg daily),
discontinuation was less likely with low-dose paroxetine,
which was also associated with a significant improvement
in sleep compared with placebo.
Venlafaxine (Effexor) has not only been studied in larger
populations than fluoxetine and paroxetine, but efficacy
and safety data are established for 13 weeks (in contrast
to half that duration for fluoxetine and paroxetine).
Evans et al. (Obstet Gynecol (2005): Management
of Postmenopausal Hot Flushes With Venlafaxine Hydrochloride:
A Randomized, Controlled Trial) found that extended-release
venlafaxine, 75 mg per day, was an effective treatment
for postmenopausal hot flushes in otherwise healthy
women, with only three side effects, dry mouth, sleeplessness,
and decreased appetite, significantly more frequent
in the venlafaxine group than in the control group.
Ladd et al. (Depress Anxiety (2005): Venlafaxine
in the treatment of depressive and vasomotor symptoms
in women with perimenopausal depression) also
found that venlafaxine treatment improves overall well-being,
reduces depressive symptoms, and may diminish baseline
vasomotor symptoms in depressed perimenopausal women.
(2) These antidepressants are generally well tolerated,
with the most common adverse events being dry mouth,
constipation, decreased appetite, and nausea, so agent
selection should be by tolerability and the slight but
significant differences in adverse-effect profiles.
(3) Finally, Breast Cancer Watch warns that these
agents should be viewed narrowly solely for potential
relief of hot flashes: it is not determined whether
they may exhibit negative impact on other menopausal
symptoms such as vaginal dryness, given their anticholinergic
effects which, although significantly less marked than
exhibited in the older tricyclic class, are nonetheless
still nontrivial in degree, or on cardiovascular function
(again, although cardiovascular side effects are fewer
with these newer agents than with tricyclics, they nonetheless
need to be assessed and monitored). In addition, reductions
in hot flash frequency are typically in the order of
30% to possibly as high as 50%, admittedly significant
relief, but in no wise comparable to HRT with a proven
efficacy of 85%+; patients therefore being treated with
SSRIs for hot flashes must be counseled to lower there
expectations of the level of relief achievable (so De
Sloover Koch, Ann Pharmacother (2004): Selective
Serotonin-Reuptake Inhibitors for the Treatment of Hot
Flashes) concluded from a review of the literature
that SSRIs are generally "modestly successful in
reducing the frequency and severity of hot flashes")
in both in perimenopausal and postmenopausal women,
and in women with breast cancer.
- The
Problem of SSRI-induced Sexual Dysfunction
It is now well-known that certain antidepressants can
both (1) cause de-novo sexual dysfunction in a person
with no such dysfunction prior to treatment, or (2)
further worsen preexisting adverse sexual symptoms,
thus causative of SD (sexual dysfunction). SD appears
to be independent of the not infrequent association
of diminished sexual interest in depressive states,
both unipolar and bipolar.
These effects are commonly and most frequently observed
with SSRIs (selective serotonin reuptake inhibitors),
and it would appear that their incidence has been underestimated
until recently. SD may manifest for men or women differentially
across symptoms such as erectile dysfunction, diminished
libido and delayed/attenuated or absent orgasm (dysorgasmia
or anorgasmia).
- Treating SD
- Drug Holidays:
The Rothschild study i(J Clin Psychiatry: Sexual
side effects of antidepressants) found that
for patients with sexual dysfunction secondary to SSRIs,
a two-day drug holiday (skipping Friday/ Saturday, re-commencing
Sunday afternoon) improved sexual function with no loss
in antidepressant efficacy [for those on paroxetine
(Paxil) and sertraline (Zoloft), but not for those on
fluoxetine (Prozac), probably due to the later's relatively
longer half-life].
- Treating SD - Buspirone:
The Norden study (Depression: Buspirone
treatment of sexual dysfunction associated with selective
serotonin reuptake inhibitors) showed improvement
in SD with adjunctive dosing of the anxiolytic buspirone
(Buspar), earlier shown in case reports to reverse sexual
side effects, at 15 - 60 mg/daily, with more improvement
at the higher range during four weeks of treatment.
(It is interesting to note that a later RCT study of
buspirone, amantadine, and placebo, found significant
and equivalent improvement in all three arms of the
study [see Michelson et al, J Am Psychiatry: Female
sexual dysfunction associated with antidepressant administration,
although Breast Cancer Watch notes that the study
may have encountered some methodological constraints,
including a subject population limited to pre-menopausal
women, so further studies are needed to be wholly determinative]).
Buspirone's efficacy in SD treatment may be consequent
to its dopaminergic activity, or its serotonin-1A receptors
partial agonist effect, or possibly its direct suppression
of SSRI-induced prolactin elevation (buspirone's a2
antagonist major metabolite is known to facilitate sexual
behavior in animals).
- Treating
SD - Gingko Biloba:
Cohen et al [J Sex Marital Ther: Gingko
biloba for antidepressant-induced sexual dysfunction]
found improvement of SSRI-induced SD through administration
of Gingko biloba within an effective range of 60 - 240
mg/daily. However, it should be noted that two later
studies [Ashton et al, Am J Psychiatry: Antidepressant-Induced
Sexual Dysfunction and Ginkgo Biloba, and Kang
et al, Hum Psychopharmacol: A
placebo-controlled, double-blind trial of Ginkgo biloba
for antidepressant-induced sexual dysfunction]
failed to confirm efficacy over placebo level, and given
methodological issues, further RCTs are needed to be
determinative.
- Treating
SD - Yohimbe:
Woodrum [Ann Pharmacother: Management
of SSRI-induced sexual dysfunction] reports
on the efficay of the natural presynaptic a2-blocker
Yohimbe in treating SSRI-induced decreased libido and
anorgasmia, in an on demand scenario: using a dose from
5.4 to 16.2 mg, taken as needed 1 to 4 hours before
intended sexual intercourse. (See also the comprehensive
review by Adimoelja in Int J Androl: Phytochemicals
and the breakthrough of traditional herbs in the management
of sexual dysfunctions).
-
Treating SD - Mirtazapine
and Nefazodone:
The postsynaptic serotonin antagonist mirtazapine (Remeron),
a relatively new antidepressant, is a potent 5-HT2 and
5-HT3 antagonist, with additional a2-antagonistic properties;
therefore, mirtazapine’s antagonistic action can
improve or resolve adverse SD (probably mediated through
5-HT2 stimulation); see Farah in J Clin Psychiatry:
Relief
of SSRI-induced sexual dysfunction with mirtazapine
treatment and Zajecka in J Clin Psychiatry:
Strategies
for the treatment of antidepressant-related sexual dysfunction).
Both mirtazapine and nefazodone (Serzone) as postsynaptic
serotonin antagonists, appear to have minimal, if any,
adverse effect on sexual functioning, and hence these
antidepressants may be viable first-line agents for
treating depression in scenarios requiring avoidance
of SD, and have furthermore been shown to improve SSRI-induced
sexual side effects when used in an additive antidote
role. On nefazodone-aided reduction in SD, see Cleman
et al, J Clin Psychiatry: Nefazadone
and the treatment of nonparaphilic compulsive sexual
behavior: A retrospective study). As noted above,
Michelson et al failed to confirm efficacy of mirtazapine
over placebo [J Am Psychiatry: Female
sexual dysfunction associated with antidepressant administration],
but Breast Cancer Watch notes that the study
may have encountered some methodological constraints,
including a subject population of limited to pre-menopausal
women, so further studies are needed to be wholly determinative.
-
Treating SD - Sildenafil:
Sidenafil (Viagra), approved for male erectile dysfunction,
is a PDE5 inhibitor (competitive inhibitor of cGMP-specific
phosphodiesterase (PDE) type 5) and so increases nitric
oxide production, yielding smooth muscle relaxation
and increased blood flow to genital tissues. Several
stdies have found proven it to reverse sexual side effects
of SSRIs {see Zajecka in J Clin Psychiatry: Strategies
for the treatment of antidepressant-related sexual dysfunction],
but recent studies have also proven efficacy in the
treatment of female sexual dysfunction [see especially
Berman et al, J Sex Marital Ther: Effect
of sildenafil on subjective and physiologic parameters
of the female sexual response in women with sexual arousal
disorder, also Caruso et al, BJOG: Premenopausal
women affected by sexual arousal disorder treated with
sildenafil: a double-blind, cross-over, placebo-controlled
study, and most recently, Berman et al, J Urol:
Safety
and efficacy of sildenafil citrate for the treatment
of female sexual arousal disorder: a double-blind, placebo
controlled study]. Its positive mechanism of
action in this context appears to be to increase blood
flow to the clitoris and vagina; usual effective dose
range appears to be 50 - 100 mg, and can be taken as
needed within 30 - 60 minutes of intended sexual activity.
- Treating
SD - Bupropion:
The antidepressant bupropion (Wellbutrin) demonstrates
norephinephrine- and dopamine-enhancing activity. The
earlier study of Clayton et al, J Clin Psychiatry: Substitution
of an SSRI with bupropion sustained release following
SSRI-induced sexual dysfunction had found that
bupropion alleviates SSRI-induced sexual dysfunction,
with sexual functioning improving after the addition
of bupropion SR to SSRI regimen (and continuing to improve,
after SSRI discontinuation, with bupropion SR therapy
alone), although some patients withdrew during the study
consequent to bupropion side effects. Another most recent
controlled study [Clayton, J Clin Psychiatry: A
Placebo-Controlled Trial of Bupropion SR as an Antidote
for Selective Serotonin Reuptake Inhibitor-Induced Sexual
Dysfunction, has re-confirmed these findings,
showing bupropion SR to be an effective antidote to
SSRI-induced SD, producing an increase in desire to
engage in sexual activity and frequency of engaging
in sexual activity, compared with placebo.
- Treating
SD - Fluvoxamine:
Although SSRI-induced SD is now wel-documented, it must
be countenanced that some patients exhibiting SD may
be solely, or maximally, responsive to SSRI antidepressants.
In this scenario, an earlier study of Banov had found
that the SSRI fluvoxamine (Luvox) may exhibit less SD
than other SSRIs; however, a later multicenter study
[Montejo et al, J Clin Psychiatry: Incidence
of sexual dysfunction associated with antidepressant
agents: a prospective multicenter study of 1022 outpatients]
does not support this conclusion, and an Evidncewatch
review of the literature (as of Feb., 2004) failed to
discover other confirmation.
- Treating
SD - Testosterone:
Several studies and reviews have suggested a potentially
benefial role for testosterone in the treatment of female
sexual dysfunction: Balour & Barunstein (Int J Impot
Res (2005): Testosterone
therapy in women: a review) concluded that testosterone
therapy in the low-dose regimens is efficacious for
the treatment of WSIDD (Women's Sexual Interest and
Desire Disorder) in postmenopausal women who are adequately
estrogenized, and that based on the evidence of current
studies, it is reasonable to consider testosterone therapy
for a symptomatic androgen-deficient woman with WSIDD.
Furthermore, NAMS has published a position statement
(Menopause (2005): The
role of testosterone therapy in postmenopausal women:
position statement of The North American Menopause Society)
concluding that postmenopausal women with decreased
sexual desire associated with personal distress and
with no other identifiable cause may be candidates for
testosterone therapy, although testosterone treatment
without concomitant estrogen therapy could not be recommended
because of a lack of evidence, but they caution that
testosterone therapy is contraindicated in women with
breast or uterine cancer or in those with cardiovascular
or liver disease.
Somewhat more guarded conclusions were reach in a recent
NIH Consensus Statement (Ann Intern Med (2005): National
Institutes of Health State-of-the-Science Conference
Statement: Management of Menopause-Related Symptoms):
combination oral testosterone–estrogen (as opposed
to estrogen only) yielded improvements in libido, but
with no added benefits for vaginal dryness or sleep
disturbances; in addition transdermal testosterone in
women with surgical menopause also yielded improved
sexual symptoms. In both cases, the adverse effects
of testosterone therapy included acne, hirsutism, and
weight gain. However NIH notes that the long-term risks
of taking testosterone have not been studied in this
population.
- Breast
Cancer Watch Warning: SSRIs and Tamoxifen Metabolism
Tamoxifen is converted into its active metabolites 4-hydroxy-tamoxifen,
endoxifen, and other active metabolites, in the liver
by the CYP2D6 liver enzyme, one of many CYP enzymes
that are part of the liver's P450 detoxification pathway,
and primarily responsible for the metabolism of tamoxifen
into its active metabolites (plasma concentrations of
these active metabolites are associated with the cytochrome
P450 (CYP) 2D6 genotype). We now know that the efficacy
of tamoxifen therapy for the treatment of breast cancer
exhibits wide individual variation among individuals
that appears to be genetic, with some women able to
convert tamoxifen into active metabolites more effectively
than others; women with the normal gene produce somewhere
in the order of two to four times as much of active
metabolites as those with with the variant that is a
relatively ineffective tamoxifen active metabolite converter.
Working from the fact that SSRI ( selective serotonin
reuptake inhibitor) antidepressants are know to be CYP2D6
enzyme inhibitors, Stearns and colleagues (J Natl Cancer
Inst (2003): Active
Tamoxifen Metabolite Plasma Concentrations After Coadministration
of Tamoxifen and the Selective Serotonin Reuptake Inhibitor
Paroxetine) identified a previously unrecognized
active metabolite of tamoxifen, named by them endoxifen,
and found that endoxifen was present in substantially
higher concentrations than 4-hydroxy-tamoxifen, but
after administration of the SSRI antidepressant paroxetine
(Paxil) treatment, endoxifen levels decreased, but levels
of 4-hydroxy-tamoxifen did not. At that time, the researchers
suggested that CYP2D6 genotype and drug interactions
should be considered in women treated with tamoxifen;
however, the precise clinical implications of low circulating
endoxifen concentrations are not fully known (Goetz
et al., J Natl Cancer Inst (2003): A
Hot Flash on Tamoxifen Metabolism).
Some of the same researchers (Stearns et al., J Clin
Oncol (2004):
The effect of CYP 2D6 genotype and CYP2D6 inhibitors
on tamoxifen) have revisted this problem, reporting
preliminary data from an ongoing prospective study to
confirm the original findings. The later study found
that certain CYP 2D6 genotypes, as well as the use of
the CYP 2D6 inhibitor SSRI antidepressants sertraline
and paroxetine strongly influence tamoxifen conversion
to endoxifen. However Breast Cancer Watch notes that
although endoxifen levels were affected adversely, there
was no change in concentrations of tamoxifen itself
or its other metabolites, thus still leaving unclear
the clinical implications of these results (the authors
concluded that therefore the findings are still insufficiently
powered to dictate any change to prescribing practices
at present).
- Breast Cancer Watch
further notes that although the SSRIS sertraline
and paroxetine as CYP2D6 inhibitors were associated
with low concentrations of endoxifen, the dual
mechanism
agent venlafaxine, a serotonin/norepinephrine reuptake
inhibitor (SNRI), was not, suggesting that the SNRI
venlafaxine (Effexor) in particular may
be a potential workaround for breast cancer patients
requiring hot flash relief (although we note that
gabapentin is also an effective alternative choice;
see below our discussion of neuroactive agents).
Some confirming evidence of this advantage for venlafaxine
was recently put forward by Jin et al. in their
prospective observational study (J Natl Cancer Inst
(2005): CYP2D6
Genotype, Antidepressant Use, and Tamoxifen Metabolism
During Adjuvant Breast Cancer Treatment)
which found that plasma endoxifen concentration
was only slightly decreased by venlafaxine, a weak
inhibitor of CYP2D6, but substantially reduced in
subjects who took paroxetine (a potent inhibitor
of CYP2D6), with again the magnitude of the reduction
in plasma endoxifen concentration associated with
CYP2D6 inhibitor use dependent on the CYP2D6 genotype.
The researchers however prudently note that although
SSRIs may affect tamoxifen’s antitumoral efficacy
or its side effects, this hypothesis requires further
testing in actual clinical trials.
- Although therefore
the SNRI venlafaxine (Effexor) is a
weak CYP2D6 inhibitor, the two other SNRIs
mirtazapine (Remeron) and duloxetine
(Cymbalta) both appear to have significant
potential interaction across CYP2D6 and hence should not
be coadministered with tamoxifen.
- A systematic review
of the literature, as of 12/21/07, for potentially
adverse significant interactions between tamoxifen
CYP2D6 metabolism and any antidepressant including
SSRIs, SNRIs, tricyclics (TCAs), and various atypicals
such as bupropion (Wellbutrin),
nefazodone (Serzone), among others, has failed
to uncover decisive evidence of any safe agent outside
of what is already known solely on venlafaxine
(Effexor), and the FDA-approval-pending venlafaxine
analog, desvenlafaxine (Pristiq).
Breast Cancer Watch Guideline:
Hot Flash Relief in Breast
Cancer Patients
Based on the above findings, we suggest that
the evidence supports a first-line trial of gabapentin
900mg./day, followed by a trial of low-dose (37.5
mg/day) venlafaxine (or extended-release venlafaxine
at 75mg./day) if patient fails to achieve sufficient
relief on gabapentin.
- Neuroacive
Agents:
Gabapentin
NAMS indicates that gabapentin may be beneficial at
a daily dose of 300 mg, initiating treatment at 100
mg for women older than 65, thereafter titrating gradually
to therapeutic dosage. However, recent findings suggest
this recommendation (re gabapentin at 300mg/dialy) is
in error; see below.
Breast Cancer Watch Commentary:
Gabapentin:
The findings of a recent study of Pandya et al. (Lancet
(2005): Gabapentin
for hot flashes in 420 women with breast cancer: a randomised
double-blind placebo-controlled trial) help
to explain some of the earlier inconclusive research
on gabapentin: two doses of gabapentin were tested in
breast cancer patients, 300 mg/daily and 900 mg/dialy,
with only the higher dose of gabapentin being associated
with significant decreases in hot-flash frequency and
severity, the demonstrated efficacy allowing the drug
to be deployed for treatment of hot flashes in women
with breast cancer; significantly, gabapentin at 900mg/daily
was able to reduce the frequency of hot flashes by 41%
and the severity of hot flashes by 49%, and even at
this higher dose, it was very well tolerated. This is
in substantial agreement with the earlier findings of
Loprinzi et al. (Mayo Clin Proc (2002): Pilot
Evaluation of Gabapentin for Treating Hot Flashes)
and Guttuso et al. (Obstet Gynecol (2003): Gabapentin’s
Effects on Hot Flashes in Postmenopausal Women: A Randomized
Controlled Trial) . See also Haimov-Kochman
& Hochner-Celnikier (Acta Obstet Gynecol Scand (2005):
Hot
flashes revisited: Pharmacological and herbal options
for hot flashes management. What does the evidence tell
us?).
Indeed, Sireesha Reddy at the University of Rochester
and coresearchers (Reddy et al., Obstet Gynecol (2006):
Gabapentin,
Estrogen, and Placebo for Treating Hot Flushes - A Randomized
Controlled Trial) conducted an RCT comparing
gabapentin, titrated to 2,400 mg/daily directly with
estrogen, as 0.625 mg/daily of conjugated estrogens,
for the treatment of hot flashes for 12 weeks, finding
that gabapentin was as effective as estrogen in the
treatment of postmenopausal hot flashes.
Clonidine
Although it appears to be less effective than antidepressants
and gabapentin, it may be of some benefit at an oral
dosage of 0.05 mg twice daily, or as a patch dosage
at 0.10 mg/day.
Methyldopa
NAMS recommends against the antihypertensive agent methyldopa
due to substantial adverse effects.
Bellargal
NAMS recommends against this mixture of belladona alkaloids,
ergotamine tartrate, and phenobarbital due to substantial
adverse effects.
- Veralipride
+ Raloxifene:
Although raloxifene (Evista) itself has not proved to
benefit vasomotor menopausal symptoms, the antidopaminergic
agent veralipride, which also demonstrates antigonadotrpic
activity, induces significant reduction of such symptoms,
especially hot flashes; see the early findings of Mellis
et al., Obstet Gynecol (1988): Effects
of the dopamine antagonist veralipride on hot flushes
and luteinizing hormone secretion in postmenopausal
women), Verbeke et al., Maturitas (1988): Clinical
and hormonal effects of long-term veralipride treatment
in post-menopausal women), Boulot & Viala
(Rev Fr Gynecol Obstet (1988): A
multicenter comparison of veralipride versus placebo
in the vasomotor flushes of menopause. An evaluation
of the prolonged effect), Boukobza (Rev Fr Gynecol
Obstet (1986): Efficacy
and tolerance of veralipride in the treatment of flushing
in the menopause. A multicenter study), and
Wesel et al. (Curr Med Res Opin (1984): Veralipride
versus conjugated oestrogens: a double-blind study in
the management of menopausal hot flushes), with
hot flash relief persisting for at least 3 months following
administration.
These early findings led Morgante et al. (Gynecol Endocrinol
(2004): Veralipride
administered in combination with raloxifene decreases
hot flushes and improves bone density in early postmenopausal
women) to more recently investigate whether
the combination of raloxifene and veralipride in postmenopausal
women with high osteoporosis risk in whom hormone therapy
was contraindicated may also benefit vasomotor symptoms;
two regimens were tested: raloxifene (60 mg/day) continuously
+ veralipride (100 mg/day) on alternate days, or on
alternate months, finding that both regimens led to
a significant reduction of hot flushes after 3 and 6
months, along with a significant improvement in bone
density (as per BMD), with no significant changes of
prolactin levels.
Breast Cancer Watch
Note:
However, we observe in connection with the recent Morgante
study cited above, that (1) the action of veralipride
may be mediated by a not wholly desirable increase in
estradiol (as found in the study of David et al., Am
J Obstet Gynecol (1988): Veralipride:
alternative antidopaminergic treatment for menopausal
symptoms), and (2) it is indeterminate from
the study of the combination of veralipride with raloxifene,
whether raloxifene was additive or synergistic to the
well-known effects of veralipride on vasomotor symptoms,
or merely played its typical role as an osteoporotic
agent with BMD benefit.
- Diet:
NAMS does not directly address specific dietary habits
in association with menopause relief; however the population
study of Park et al. (Taehan Kanho Hakhoe Chi (2004):
Association
of Diet with Menopausal Symptoms in Korean Middle-aged
Women) suggests that higher intake of fishes,
seaweeds, and vegetable oils were inversely associated
with bothersome levels of vasomotor symptoms, and that
women with higher intake of yellow-green vegetables
and lower intake of coffee, confectionery, and processed
foods reported lower hot flush rate.
- Antidepressants: For Hot
Flashes, and Some Issues
For women who are not candidates for estrogen
therapy, including breast cancer survivors, NAMS recommends
the antidepressants venlafaxine
(37.5-75.0 mg/day), paroxetine
(12.5-25.0 mg/day), or fluoxetine
(20.0 mg/day); onset of benefit appears to be
relatively rapid (within 1 to 2 weeks). NAMS advises
initiating treatment with very low doses, with increases
if necessary over weeks, and cessation under gradual
tapering. This is partially confirmed (Biglia et al.,
Maturitas (2005): Evaluation
of low-dose venlafaxine hydrochloride for the therapy
of hot flushes in breast cancer survivors)
for low dose (37.5 mg/day) venlafaxine as an
effective treatment for the relief of vasomotor symptoms
in patients previously treated for breast cancer, as
well as in those patients using tamoxifen as adjuvant
therapy, with minimal side effects. Note that improvement
in hot flashes may require over 8 weeks of use.
There have recently been several pilot studies examining
the role of other antidepressants on menopausal symptoms:
Barton et al. (J Support Oncol (2003):
Pilot
evaluation of citalopram for the relief of hot flashes)
found that citalopram (Celexa), during the first
week of treatment at 10 mg/day, with 20 mg/day for the
following three weeks, significantly reduced hot flashes,
with additional benefits of decreased anger, tension
and depression, as well as improved mood; and Perez
et al. (J Support Oncol (2004):
Pilot
evaluation of mirtazapine for the treatment of hot flashes)
found that mirtazapine (Remeron) at a dose of
7.5 mg at bedtime, increased to 15 mg at week 3, 30
mg at week 4, and either 15 mg or 30 mg at week 5 by
patient choice, provided significant relief from hot
flashes, with only increases in appetite and dry mouth
as typical side effects.
Breast
Cancer Watch
Commentary on Antidepressants:
The NAMS findings as to the modest efficacy (mean reduction,
50-67%, less than that observed with estrogen therapy
(90%)) of antidepressants - in particular, Effexor (Venlafaxine),
Prozac (Fluoxetine), and Paxil (Paroxetine) - are cross-supported
in the literature: see Koch (Ann Pharmacother (2004):
Selective
Serotonin-Reuptake Inhibitors for the Treatment of Hot
Flashes) and Hackley
et al. (Medscape Review: J Midwifery Womens Health:
Managing
Menopausal Symptoms After the Women's Health Initiative).
(1) On the extremes, we note that Breast
Cancer Watch finds least compelling the results
on fluoxetine (Prozac) and citalopram (Celexa) (see
the Suvanto-Luukkonen et al. Menopause (2005):
Citalopram
and fluoxetine in the treatment of postmenopausal symptoms:
a prospective, randomized, 9-month, placebo-controlled,
double-blind study, which found that citalopram
and fluoxetine have little effect on hot flushes); most
compelling are the results on paroxetine (Paxil)and
venlafaxine (Effexor) (Evans et al., Obstet Gynecol
(2005): Management
of Postmenopausal Hot Flushes With Venlafaxine Hydrochloride:
A Randomized, Controlled Trial) with other agents
such as sertaline (Zoloft) not appearing significantly
more effective than placebo in this regard. A recent
RCT (Stearns et al., J Clin Oncol (2005):
Paroxetine
Is an Effective Treatment for Hot Flashes: Results From
a Prospective Randomized Clinical Trial) reconfirmed
earlier findings as to the efficacy of paroxetine in
the treatment of hot flashes in women with or without
prior breast cancer, noting that although efficacy was
similar between two tested doses (10mg and 20mg daily),
discontinuation was less likely with low-dose paroxetine,
which was also associated with a significant improvement
in sleep compared with placebo.
Venlafaxine (Effexor) has not only been studied in larger
populations than fluoxetine and paroxetine, but efficacy
and safety data are established for 13 weeks (in contrast
to half that duration for fluoxetine and paroxetine),
and as Mom et al. (Crit Rev Oncol Hematol (2005): Hot
flushes in breast cancer patients) observed,
of the several non-hormonal options, the selective serotonin-reuptake
inhibitor (SSRI) venlafaxine is the most effective in
breast cancer patients. Evans et al. (Obstet Gynecol
(2005): Management
of Postmenopausal Hot Flushes With Venlafaxine Hydrochloride:
A Randomized, Controlled Trial) found that extended-release
venlafaxine (Effexor-XR), 75 mg per day, was an effective
treatment for postmenopausal hot flushes in otherwise
healthy women, with only three side effects, dry mouth,
sleeplessness, and decreased appetite, significantly
more frequent in the venlafaxine group than in the control
group. Ladd et al. (Depress Anxiety (2005): Venlafaxine
in the treatment of depressive and vasomotor symptoms
in women with perimenopausal depression) also
found that venlafaxine treatment improves overall well-being,
reduces depressive symptoms, and may diminish baseline
vasomotor symptoms in depressed perimenopausal women.
(2) These antidepressants are generally well tolerated,
with the most common adverse events being dry mouth,
constipation, decreased appetite, and nausea, so agent
selection should be by tolerability and the slight but
significant differences in adverse-effect profiles.
(3) Finally, Breast Cancer
Watch warns
that these agents should be viewed narrowly solely for
potential relief of hot flashes: it is not determined
whether they may exhibit negative impact on other menopausal
symptoms such as vaginal dryness, given their anticholinergic
effects which, although significantly less marked than
exhibited in the older tricyclic class, are nonetheless
still nontrivial in degree, or on cardiovascular function
(again, although cardiovascular side effects are fewer
with these newer agents than with tricyclics, they nonetheless
need to be assessed and monitored). In addition, reductions
in hot flash frequency are typically in the order of
30% to possibly as high as 50%, admittedly significant
relief, but in no wise comparable to HRT with a proven
efficacy of 85%+; patients therefore being treated with
SSRIs for hot flashes must be counseled to lower there
expectations of the level of relief achievable (so De
Sloover Koch, Ann Pharmacother (2004): Selective
Serotonin-Reuptake Inhibitors for the Treatment of Hot
Flashes) concluded from a review of the literature
that SSRIs are generally "modestly successful in
reducing the frequency and severity of hot flashes")
in both in perimenopausal and postmenopausal women,
and in women with breast cancer.
- Breast Cancer Watch Warning:
SSRIs and Tamoxifen Metabolism
There are some critical issues concerning the
potential inhibition of the antitumor efficacy of tamoxifen
by certain antidepressants, particularly SSRIs: for
a full discussion, with warnings and recommendations,
consult our SSRI
Antidepressants and Tamoxifen.
- Breast
Cancer Watch Commentary: Gabapentin (Neurontin):
The findings of a recent study of Pandya
et al. (Lancet (2005): Gabapentin
for hot flashes in 420 women with breast cancer: a randomised
double-blind placebo-controlled trial)
help to explain some of the earlier inconclusive
research on gabapentin (Neurotin): two doses of gabapentin
were tested in breast cancer patients, 300 mg/daily
and 900 mg/daily, with only the higher dose of gabapentin
being associated with significant decreases in hot-flash
frequency and severity; significantly, gabapentin at
900mg/daily was able to reduce the frequency of hot
flashes by 41% and the severity of hot flashes by 49%,
and even at this higher dose, it was very well tolerated.
This is in substantial agreement with the earlier findings
of Loprinzi et al. (Mayo Clin Proc (2002):
Pilot
Evaluation of Gabapentin for Treating Hot Flashes)
and Guttuso et al. (Obstet Gynecol (2003):
Gabapentin’s
Effects on Hot Flashes in Postmenopausal Women: A Randomized
Controlled Trial) . See
also Haimov-Kochman & Hochner-Celnikier (Acta Obstet
Gynecol Scand (2005): Hot
flashes revisited: Pharmacological and herbal options
for hot flashes management. What does the evidence tell
us?).
Indeed, Sireesha Reddy at the
University of Rochester and coresearchers (Reddy et
al., Obstet Gynecol (2006): Gabapentin,
Estrogen, and Placebo for Treating Hot Flushes - A Randomized
Controlled Trial) conducted an RCT comparing
gabapentin, titrated to 2,400 mg/daily directly with
estrogen, as 0.625 mg/daily of conjugated estrogens,
for the treatment of hot flashes for 12 weeks, finding
that gabapentin was as effective as estrogen in the
treatment of postmenopausal hot flashes.
- Breast
Cancer Watch Guideline
Hot Flash Relief in Breast Cancer Patients
Based on the above findings, we suggest that the evidence
supports a first-line trial of gabapentin 900mg./day,
followed by a trial of low-dose (37.5 mg/day) venlafaxine
(or extended-release venlafaxine at 75mg./Day) if patient
fails to achieve sufficient relief on gabapentin. Furthermore,those
breast cancer patients who fail to realize significant
relief from either of these interventions may consider
a trial of tibolone if available (not presently
available in the US), evidence for which is given immediately
below.
Note: Although Breast Cancer
Watch feels that the balance of the evidence
strongly suggests the safety and efficacy of tibolone
for relief of vasomotor menopausal symptoms and for
anti-osteoporotic activity in women with breast cancer,
wholly dispositive determination awaits the completion
of Organon's LIBERATE (Livial Intervention following
Breast cancer: Efficacy, Recurrence And Tolerability
Endpoints) trial, expected to report by end of 2007.
However, we note that all recent published findings
to date continue to confirm the safety of tibolone deployment
in the breast cancer setting.
In terms of both safe and effective relief of hot flashes
and other vasomotor symptoms of menopause in the breast
cancer setting, in addition to the neuroagent gabapentin
and the antidepressant venlafaxine (both documented
above), the balance of the evidence finds both efficacy
and safety for the herbal black cohosh extract,
which significantly reduced both the frequency and the
severity of hot flashes, and which also exhibited significant
benefit on symptoms of both anxiety and depression;
furthermore it has been studied explicitly in breast
cancer populations and found not only to be not be adversely
estrogenic, but preliminary results suggest potentially
beneficial estrogen-antagonistic
/ antiproliferative activity (see below for all confirming
studies). Howver, as we note below, it may interference
with either the efficacy or safety of certain chemotherapies,
and so caution is advised (see full discussion below).
- Black Cohosh
- Black
Cohosh: Reduction of Vasomotor Symptoms
Reported (T. Low (Dog) et al., Menopause (2003):
Critical
evaluation of the safety of Cimicifuga racemosa
in menopause symptom relief) is a critical
study that, on the basis of postmarketing surveillance,
the results of clinical trials, and toxicology reviews,
". . . clearly supports the safety of specific
Cimicifuga extracts [black cohosh] . . . for use
in women experiencing menopausal symptoms and as
a safe alternative for women in whom estrogen therapy
is contraindicated". Studied was the proprietary
isopropanolic preparation of black cohosh, Remifemin.
The principal researcher, T. Low Dog (Am J Med (2005):
Menopause: a review of botanical dietary supplements)
recently updated these findings in late 2005, concluding
again that the majority of studies indicate that
extract of black cohosh (Actaea racemosa L.) improves
menopause-related symptoms . . . and that it is
well tolerated and that adverse events are rare
when it is used appropriately. Similarly, the review
of Geller and Studee (J Womens Health (Larchmt)
(2005): Botanical
and dietary supplements for menopausal symptoms:
what works, what does not) concluded that
the evidence to date suggests that black cohosh
is safe and effective for reducing menopausal symptoms,
primarily hot flashes and possibly mood disorders.
Frei-Klener et al. (Maturitas (2005): Cimicifuga
racemosa dried ethanolic extract in menopausal disorders:
a double-blind placebo-controlled clinical trial)
found in a subgroup analysis that Cimicifuga racemosa
extract was superior to placebo in patients with
menopausal disorders of at least moderate intensity.
Again, Vermes et al. (Adv Ther (2005): The
effects of remifemin on subjective symptoms of menopause)
found the isopropanol extract of C racemosa to be
effective in the alleviation of menopausal symptoms.
Indeed, cimicifuga
racemosa (isopropanolic aqueous extract of black
cohosh) at 40mg/daily was found to be a viable alternative
to low-dose transdermal estradiol, given as 25 microgram
every 7 days plus dihydrogesterone 10 mg/day for
the last 12 days of a 3-month estradiol treatment
(Nappi et al., Gynecol Endocrin (2005): Efficacy
of Cimicifuga racemosa on climacteric complaints:
a randomized study versus low-dose transdermal estradiol).
Both agents significantly reduced the number of
hot flushes per day and vasomotor symptoms starting
at the first month of treatment, maintaining a positive
effect throughout the 3 months of observation, without
any significant difference between the two treatments;
equivalent effects were found in the significant
reduction of both anxiety and depression and for
both agents following 3 months usage,and endometrial
thickness was not affected by either agent.
These findings accords well with similar findings
in other studies. Winterhoff et al. (Maturitas (2003):
Cimicifuga extract BNO 1055: reduction of hot flushes
and hints on antidepressant activity) demonstrated
that Cimicifuga extracts induce a reduction of hot
flush frequency and some hint of antidepressant
activity. In addition, Munoz et al. (Maturitas (2003):
Cimicifuga racemosa for the treatment of hot flushes
in women surviving breast cancer) examined
the effect of an Cimicifuga racemosa compound (CR
BNO 1055) on hot flushes induced by tamoxifen adjuvant
therapy in young premenopausal breast cancer survivors,
an important issue given that hot flushes are the
most frequent adverse reaction to tamoxifen adjuvant
therapy in breast cancer survivors. They found that
the coadministration of tamoxifen plus CR BNO 1055
for a year allowed significant and satisfactory
reduction in both the number and severity of hot
flushes.
Most recently, Uebelhack et al. (Obstet Gynecol
(2006): Black
Cohosh and St. John’s Wort for Climacteric
Complaints: A Randomized Trial) conducted
a double-blind randomized placebo-control study
to investigate the efficacy of a combination of
isopropanolic black cohosh (Cimicifuga racemosa)
and ethanolic St. John’s wort (Hypericum perforatum)
extracts in women with climacteric complaints with
pronounced psychological symptoms, finding the combination
safe and effective in alleviating climacteric complaints,
including the related psychological component. And
Stacie Geller and Laura Studee at the National Center
of Excellence in Women's Health, University of Illinois,
recently reviewed the literature on black cohosh
efficacy (Geller & Studee, Maturitas (2006):
Contemporary
alternatives to plant estrogens for menopause),
concluding that black cohosh appears to be one of
the most effective botanicals for relief of vasomotor
menopausal symptoms, with a similar
conclusion of efficacy for menopausal symptomology
in the recent evidence-based
review of Cathi Dennehy at UCSF (J Midwifery Womens
Health (2006): The
Use of Herbs and Dietary Supplements in Gynecology:An
Evidence-Based Review).
Breast Cancer Watch
notes that black cohosh, and other CAM agents for
relief of vasomotor menopausal symptomology ere
evidenced and intended for short-term use, typically
6 months, in keeping with the latest NAMS guidelines
(Menopause (2004): Treatment
of menopause-associated vasomotor symptoms: position
statement of The North American Menopause Society
[pdf]).
Polytherapy with Black
Cohosh, Lignans and Isoflavones
Italian researchers Annalidia Sammartino and colleagues
conducted a double-blind, randomized, placebo-controlled
trial (Sammartino et al. Gynecol Endocrinol (2006)
: Short-term
effects of a combination of isoflavones, lignans
and Cimicifuga racemosa on climacteric-related symptoms
in postmenopausal women: A double-blind, randomized,
placebo-controlled trial ) to assess the
short-term effects of a combination of black cohosh
(Cimicifuga racemosa), isoflavones, and lignans
on acute climacteric-related symptoms in postmenopausal
women, leveraging the component's unique pharmacokinetic
properties wherein isoflavones are absorbed faster
than lignans, while lignans are removed later, yielding
a better reduction of postmenopausal symptoms over
a 24-hour period, and finding significant efficacy
after 3 months of treatment.
- Black Cohosh:
Osteoprotective Activity
It is known that black cohosh extracts do not exhibit
undesirable uterine effects, such as endometrium
growth stimulation or uterine bleeding. However,
until recently any osteoprotective effects has been
an open question, now resolved by the small but
well-designed study of Wuttke et al. (Maturitas
(2003): The
Cimicifuga preparation BNO 1055 vs. conjugated estrogens
in a double-blind placebo-controlled study: effects
on menopause symptoms and bone markers),
where it was found that an extract of black cohosh
rhizome (CR BNO 1055) improved climacteric complaints,
induced positive estrogenic effects in both the
vagina (relief of vaginal atrophy and dryness) and
on bone metabolism, without unfavorable uterine
effects. Indeed, black cohosh and conjugated estrogens
had comparable beneficial effects on markers of
bone metabolism (starting at at week 12). And more
impressively, bone-specific alkaline phosphatase,
the marker for bone formation, was unchanged in
the placebo and the conjugated estrogens group,
but was significantly increased in the black cohosh
group. It appears that black cohosh has bone osteoprotective
effects via increasing osteoblast activity (osteoblast
cells initiate bone formation).
And the lack of black cohosh-induced uterine stimulation,
as evaluated by endometrial thickness, suggests
that it is improbable that black cohosh will stimulate
endometrial cancer. The authors speculate that black
cohosh may exert mild estrogenic effects, without
affecting the uterus, in the brain, bones, and the
vaginal epithelium, by virtue of containing substances
with selective estrogen receptor modulators, but
this view of black cohosh as strogenic in activity
has subsequently been disproved (see below).
Warning: This study notes, and Breast
Cancer Watch has found independent confirmation
elsewhere in the literature, that both conjugated
estrogens and black cohosh tend to increase triglycerides,
and this may require accommodation through lipid
control treatment. In addition, Breast Cancer Watch
does not find compelling isolated reports (one by
Lontos et al., MJA: Acute
liver failure associated with the use of herbal
preparations containing black cohosh) of
acute liver failure associated with black cohosh:
as pointed out by Thomsen et al. (Med J Aust (2004):
Acute
liver failure associated with the use of herbal
preparations containing black cohosh), also
ingested was an herb (ground ivy) containing a known
strong hepatotoxin, pulegone. The safety profile
of black cohosh has been exemplary, and after more
than 350 million daily doses sold, no confirmed
hepatotoxic effects have presented.
Finally, an isopropanolic extract from the rhizomes
of Cimicifuga racemosa (black cohosh) was found
to enhance differentiation and increase the OPG-to-RANKL
ratio of normal human osteoblasts, effects that
contribute to the positive skeletal effects of black
cohosh (Viereck et al., J Bone Miner Res (2005):
Isopropanolic
Extract of Black Cohosh Stimulates Osteoprotegerin
Production by Human Osteoblasts).
- Black Cohosh:
Issue of Breast Cancer
In addition to the Low Dog study, there have been
several recent reports confirming that black cohosh
is safe, effective and non-estrogenic (a safety
review of black cohosh in the January issue of Menopause
supported the safety of black cohosh and a report
in the November 2002 issue of Annals of Internal
Medicine concluded that black cohosh is one
of the only herbal remedies shown to be effective
for menopausal symptoms, especially hot flashes).
Breast Cancer Watch
notes that black cohosh, and other CAM agents for
relief of vasomotor menopausal symptomology ere
evidenced and intended for short-term use, typically
6 months, in keeping with the latest NAMS guidelines
(Menopause (20040: Treatment
of menopause-associated vasomotor symptoms: position
statement of The North American Menopause Society
[pdf]).
More particularly, a controlled, double-blind, randomized
trial undertaken by Liske et al. (J Womens Health
Gend Based Med (2002): Physiological
Investigation of a Unique Extract of Black Cohosh
(Cimicifugae racemosae rhizoma): A 6-Month Clinical
Study Demonstrates No Systemic Estrogenic Effect)
confirmed that the recommended dose (of the Remifemin
Menopause product) resulted in statistically significant
improvements in menopausal symptoms without affecting
hormone levels or affecting the growth of estrogen
sensitive tissues (vaginal cytology or breast).
And in animal models, GB Mahady (Nutr Rev (2003):
Is black cohosh estrogenic?) found that
extracts of black cohosh do not bind to the estrogen
receptor, up-regulate estrogen-dependent genes,
or stimulate the growth of estrogen-dependent tumors,
findings updated and re-confirmed by this same researcher
more recently (GB Mahady, Treat Endocrinol (2005):
Black
cohosh (Actaea/Cimicifuga racemosa): review of the
clinical data for safety and efficacy in menopausal
symptoms). Similarly, C. Bodinet (Breast
Cancer Res Treat (2002): Influence
of Cimicifuga Racemosa on the Proliferation of Estrogen
Receptor-Positive Human Breast Cancer Cells)
reported that black cohosh does not exhibit estrogenic
effect on estrogen-receptor positive human breast
cancer cells, and hence black cohosh "treatment
may be a safe, natural remedy for menopausal symptoms
in breast cancer".
More recently, Einbond et al. (Breast Cancer Res
Treat (2004): Growth
Inhibitory Activity of Extracts and Purified Components
of Black Cohosh on Human Breast Cancer Cells)
sought to determine whether black cohosh contains
constituents that inhibit the growth of human breast
cancer cells, and hence may prove useful in breast
cancer prevention or treatment, finding in the affirmative
several compounds with potent activity to inhibit
growth of human breast cancer cells. And Hostanska
et al. (Breast Cancer Res Treat (2004): Cimicifuga
racemosa Extract Inhibits Proliferation of Estrogen
Receptor-positive and Negative Human Breast Carcinoma
Cell Lines by Induction of Apoptosis) investigated
the antiproliferative activity of black cohosh extracts,
finding that although they appear to exerts no direct
proliferative activity, these extracts nonetheless
exert favorable effects on breast cancer cells (by
killing estrogen receptor positive MCF-7 as well
as estrogen receptor negative MDA-MB231 cells by
activation of caspases and induction of apoptosis).
And, in their important study Bodinet et al. (Menopause
(2004): Influence
of marketed herbal menopause preparations on MCF-7
cell proliferation) examined the effect
of several herbal menopausal preparations on the
proliferation of estrogen-sensitive breast cancer
cells (MCF-7) in order to determine viability of
use use in women at risk for estrogen-sensitive
breast cancer. They found that on the one hand soy,
red clover, and herbal combinations induced an increase
in the MCF-7 proliferation rates, indicating estrogen-agonistic
activity in the absence of estradiol, while on the
other hand isopropanolic black cohosh extract (Remifemin
Menopause) did not stimulate MCF-7 growth and exerted
inhibitory effects on cellular proliferation; and
no product enhanced estradiol-induced cell proliferation.
Thus, the black cohosh preparation exhibited strong
estrogen-antagonistic effects. They
conclude therefore that this lack of proliferative
effects of isopropanolic black cohosh extract on
estrogen-sensitive breast cancer cells in vitro
suggests a favorable safety profile for use in women
with a history of breast cancer, while red clover
and soy may induce cell proliferation, suggesting
caution in use in women at risk for, or with a history
of, estrogen-sensitive breast cancer. And this was
further observed by Kretzschmar et al. (J Steroid
Biochem Mol Biol (2005): No
estrogen-like effects of an isopropanolic extract
of Rhizoma Cimicifugae racemosae on uterus and vena
cava of rats after 17 day treatment) who
concluded that contrary to earlier suggestions C.
racemosa (black cohosh) does not seem to act as
an estrogen agonist, but possibly as a weak antiestrogen.
This estrogen-antagonistic
effect of black cohosh was further confirmed more
recently by Linda Saxe Einbond at Columbia University
and her coresearchers (Einbond et al., Planta Med
(2006): Actein
and a Fraction of Black Cohosh Potentiate Antiproliferative
Effects of Chemotherapy Agents on Human Breast Cancer
Cells) who evaluated whether the triterpene
glycosides present in black cohosh enhance the growth
inhibitory effects in ER- Her-2-overexpressing breast
cancer cell line (MDA-MB-453) of specific breast
cancer chemotherapy agents, doxorubicin (Adriamycin),
5-FU (5-flourouracil), and paclitaxel (Taxol), finding
that relatively low concentrations of actein or
the EtOAc fraction of black cohoshinduced synergistic
inhibition of human breast cancer cell proliferation
when combined with these different classes of chemotherapy
agents.
The effects of Remifemin (40mg/daily), the isopropanolic
extract of black cohosh on mammographic breast density
and breast epithelial proliferation in healthy,
naturally postmenopausal women with climacteric
symptoms was recently determined by Angelica Hirschberg
and colleagues at the Karolinska University Hospital
(Hirschberg et al., Menopause (2006): An
isopropanolic extract of black cohosh does not increase
mammographic breast density or breast cell proliferation
in postmenopausal women), finding no increase
in mammographic breast density, assessed by mammography
and percutaneous fine needle aspiration biopsies
at baseline and after 6 months, and no increase
in breast cell proliferation, as assessed using
the Ki-67/MIB-1 monoclonal antibody, with vaginal
ultrasound measurement of the endometrium, demonstrating
that that the isopropanolic extract of black cohosh
does not cause adverse effects on breast tissue,
and with no endometrial or general safety concerns
during 6 months of treatment.
And Karel Raus and colleagues at the Charles University
Teaching Hospital in Prague (Raus et al., Menopause
(2006): First-time
proof of endometrial safety of the special black
cohosh extract (Actaea or Cimicifuga racemosa extract)
CR BNO 1055) investigated the endometrial
safety by assessment of endometrial biopsy samples
and the tolerability and efficacy of the special
Actaea or Cimicifuga racemosa extract (CR BNO 1055),
at 40mg daily for one year, in a prospective, open-label,
multinational, multicenter study, finding no case
of hyperplasia or more serious adverse endometrial
outcome, with no increase in endometrial thickness
(measured by endovaginal ultrasonography), while
the number and intensity of hot flushes were markedly
decreased. concluding endometrial safety in terms
of lack of endometrial proliferation.
Suman Rice and coresearchers (Rive et al, Maturitas
(2006): Ethanolic
extracts of black cohosh (Actaea racemosa) inhibit
growth and oestradiol synthesis from oestrone sulphate
in breast cancer cells) tested ethanolic
extracts of black cohosh (BCE) on growth and enzyme
activity in MCF-7 and MDA-MB-123 breast cancer cells,
finding that BCE inhibited growth at the two highest
doses tested (50 and 100 µg/ml), but did not
affect the conversion of androstenedione to estradiol
but did significantly inhibited the conversion of
estrone to estradiol in MDA cells at the highest
doses (50 and 100 µg/ml) . In addition, BCE
induced a dose-dependent inhibition of the conversion
of estrone sulphate to estradiol in both cell lines,
with inhibition of human granulosa lutein (GL) cells
enzyme activity at the highest dose of BCE. The
study concludes that BCE not only inhibits growth
but inhibits the conversion of estrone sulphate
to active estradiol, which is typically considered
the preferred pathway of estradiol synthesis in
breast tissue, furthermore adding to the extensive
body of data confirming both the non-estrogenic
nature, and the anti-estrogen activity, of black
cohosh extract.
§
Issues
in Drug Interactions in Oncology
See our extensive separate coverage of potentially adverse
drug-drug, drug-herbal, and drug-CAM interactions (click
on link above).
- The Safety of Black
Cohosh: Evidence-based Methodological Issues
One study by Vicky Davis V and colleagues (Proceedings
of the AACR, Vol 44 (July 2003): Effects
of black cohosh on mammary tumor development and progression
in MMTV-neu transgenic mice. Abstract) has been
hailed throughout a gullible media as having decisively
shown that black cohosh is unsafe for use in a breast
cancer context: we've seen alarmist headlines like this:
"Black
cohosh may not be safe alternative therapy for breast
cancer patients" from OBGYN.net, "Black
cohosh used for menopausal symptoms may promote metastasis"
from Oncolink, "Breast
Cancer Warnings For Black Cohosh - May Increase Spread
of Cancer" from BreastCancer A to Z (which
still has this 2003 story as its lead on its home page!),
among dozens of others.
Single isolated studies may on occasion be found to
demonstrate or at least suggest just about anything
at all, but EBM (evidence-based medicine) examines the
cumulative weight or balance of the evidence, properly
so. And unfortunately,critical appraisal of study design
and methodology, and systematic critical review of the
evidence-base using the tools of EBM, are skills many
health professionals lack. To give one example there
is a widely cited study of Jones and colleagues in 2003
purporting to establish docetaxel (Taxotere) as superior
in efficacy over paclitaxel (Taxol); but this study
(1) is methodologically flawed, as the paclitaxel regimen
deployed was sub-optimal, and an equivalent optimal
schedule was not tested;
(2) subsequent well-controlled studies have compellingly
refuted the study's conclusion.
Yet to this date (1) surveys of oncologists show that
they believe, counterfactually, that docetaxel (Taxotere)
is superior in efficacy to paclitaxel (Taxol), and (2)
the flawed study is still incorrectly widely cited as
the final authority on the matter.
- Without going in the complexities of EBM, and it's
methodologies of systematic review, critical
appraisal, NNT (Numbers Needed to Treat)
and other tools, along with study design assessment
and quantification of the strength of the evidence,
the facts are that the overwhelming weight of the evidence,
and over 60 peer-reviewed and methodologically sound
studies, including human clinical RCTs, since the publication
of the Duquesne animal study led by Vicky Davis -and
which was:
(1) not peer-reviewed,
(2) non-clinical / non-human,
(3) methodologically compromised (see below),
(4) and whose findings have never been confirmed
or reproduced.
Cumulatively and in the balance these other findings
support:
(1) the safety of black cohosh extracts,
for both non-oncologic, and breast cancer settings in
humans;
(2) the lack of any estrogenic activity
of same;
(3) the positive benefit on vasomotor menopausal
symptoms, including hot flashes;
(4) the positive benefit on bone health
and osteoporosis;
(5) the anti-proliferative activity of same.
These are the well-evidenced facts and they are not
in dispute.
Briefly the Duquesne study sustained fatal methodological
flaws:
(1) Although it is true that one group of mice consumed
a diet containing an amount of black cohosh equivalent
to a woman ingesting 40 mg/day of a standardized black
cohosh extract (typical recommended dose for the management
of menopausal symptoms), what was omitted in the poorly
reported summary on the Johns Hopkins site was the
fact that the mice were fed this dosage of black cohosh
from the time of their sexual maturity (2 months in
such transgenic mice; a 13 month old mouse is equivalent
in age to a 50 to 60 year old human) to their maximum
age (approx. 16 months), a wholly irrational trial
procedure: this would be the equivalent of a woman
beginning this dosage of 40mg of black cohosh extract
in her teens (and why would a premenopausal women
do this?), and then continuing to take it throughout
her entire lifetime.
(2) Field experience verifies in fact that black
cohosh is typically used for relatively short duration
spans - as compared to the duration of the dosing
in the Duquesne study, the latter equivalent to at
least three to five decades.
(3) Overdosed transgenic mice bare little physiological
resemblance to human females with vasomotor menopausal
symptoms.
(4) The study is said to be, on statistical EBM appraisal,
insufficiently powered to draw conclusions in regard
to the association of black cohosh extract and increased
breast metastatic activity, even in mice (the technical
and statistical demonstration of this here would be
beyond the constraints of this forum).
It is for these reasons all major evidence-based guidelines
organizations have concluded against the methodologically
flawed and in any case isolated Duquesne study, including
the leading authority on menopausal disorders, the North
American Menopause Society (NAMS), among many others.
And notice that the Duquesne study is fatally compromised
and therefore its conclusions discredited based on the
brief simplified critical appraisal presented immediately
above, even if only the first flaw cited above were
to hold.
And as to animal research the standard for viability
should be:
(1) cross-confirmation with at least one
or more other pre-clinical studies (laboratory and/or
animal);
(2) the animal protocol should demonstrate
what's called "human-parallel" plausibility:
thus, for instance the extrapolation of lifetime equivalencies
which the Duquesne authors failed to do (had they done
so they would have realized the inapproriateness of
effects spanning half a human lifetime for a product
such as black cohosh); or another example of this would
be bone health studies in mice, almost always inappropriate
as we know that many aspects of the skeletal physiology,
bone architecture and morphology are significantly different
in rodents and humans (for example, rat bones grow in
length through their entire lifetime, while in humans,
the bone ends close relatively early in life); and still
another example in this context would be using relatively
young rats (say approx. 2 months old), where this is
inappropriate because at this age rats are still undergoing
substantial skeletal development over any study's term.
Yet each month I uncovered dozens of studies that draw
wholly illicit conclusions from these very settings.
The authors of the Duquesne study clearly demonstrated
inadequate knowledge of mice-human correlates and dissimilarities;
indeed to many researchers, the laboratory animal is
(pardon the pun) just a guinea pig, and the researchers
have little or no understanding of the complex inequivalent
dynamics, kinetics, and bio-neurologies of the animals
they are testing on.
(3) cross-confirmation in a human clinical
setting of at least an active clinical trial, of the
animal studies findings.
(4) all such studies should ethically have
to review and explicitly discuss all other evidence
impinging on the same conclusions, and plausibly
account for why their study solitarily is against the
weight of the other evidence; this is the requirement
sometimes called conflicting research accountability,
which most authors choose to ignore, as if their study
sprouted in a research vacuum.
We can sometimes relax #3 above if there is consistent
and extensive pre-clinical cross-confirmation, and all
other requirements are satisfied, but these requirements
would in general nonetheless go a long way in discarding,
correctly so, as irrelevant thousands and thousands
of studies per year that liter the medical databases
and serve only to confuse rather than clarify and focus
critical issues.
Indeed, the total number of methodologically sound
studies is actually quite small, a point related to
both your comment and an observation Pat just made on
these issues, to which I will return shortly.
-
Treatment
of Vaginal Atrophy / Dryness:
Post-menopausal diminished estrogen levels result
in numerous physiologic vaginal tissue changes: reduced
blood flow, decreased mucosal thickness, decreased
collagen content, and increased pH level, manifesting
as vaginal dryness, pruritus, dyspareunia (pain during
sexual intercourse), and recurrent infection, although
there is wide individual variation. Several effective
therapies are available (Society of Obstetricians
and Gynaecologists of Canada (SOGC (2004): The
Detection and Management of Vaginal Atrophy
[pdf]):
(1) Vaginal Estrogen Therapy
Although systemic hormone therapy is known to be effective
in the treatment of vaginal atrophy in postmenopausal
women, the recent findings on the potential negative
consequences of HRT lead many patients to seek and
prefer topical therapy. The evidence to date suggests
that an effective treatment of symptoms related to
vaginal atrophy in postmenopausal women is short-term
vaginal estrogen therapy. Topical estrogen delivery
avoids hepatic first-pass metabolism, which typically
decreases the bioavailability of oral estrogen, so
lower dosages can be deployed compared with oral therapy,
and such therapy demonstrates low acceptable levels
of systemic absorption (systemic absorption rate <
4%). In addition, short-term (less than 6 months duration)
local estrogen therapy does not require opposing progestin
treatment (evidence is limited concerning use of local
estrogen therapy for longer than six months, although
anecdotally, vaginal estrogens are often prescribed
for longer periods). Several preparations are available:
estradiol vaginal creams, tablets, and rings, and
CEE (conjugated equine estrogen) vaginal creams. The
Cochrane Review (Cochrane (2003): Local
estrogen for vaginal atrophy in postmenopausal women)
found creams, pessaries, tablets and the estradiol
vaginal ring to be equally effective for the symptoms
of vaginal atrophy.
Vaginal estrogen therapy requires caution in certain
cases: women with impaired liver function, those with
a history of breast or endometrial cancer, thromboembolic
disorder, pregnancy or active breastfeeding. Vaginal
rings (the 2 mg rings release a low 7.5 mcg/daily
dose), have a high degree of user acceptance, preference,
and tolerability, acceptability, and the ring also
demonstrates minimal incidence of development of proliferative
endometrium and endometrial hyperplasia, although
many women achieve acceptable relief with the CE cream
at lower doses than the typically prescribed 1.25
mg/daily. Thus Santen et al. (Menopause (2002): Treatment
of urogenital atrophy with low-dose estradiol: preliminary
results) demonstrated significant relief of
symptoms with the use of low levels of Estrace cream
(estradiol), finding that doses of 10 mcg/daily relieved
more than 80% of symptoms without increasing serum
levels of estrogen or causing endometrial hyperplasia,
although the usual manufacturer's recommended dose
is at least ten times as large (100 mcg/daily to 400
mcg/daily). 17-ß estradiol 25-mcg vaginal tablets
(Vagifem) are an acceptable alternative with a profile
of high efficacy, acceptability, and tolerability;
maintenance therapy requires administration of 1 tablet
into the upper vagina every 3 days via a preloaded
single-use applicator, a gel layer being formed on
contact with the vaginal mucosa, rapidly diffusion
the estradiol. The Rioux et al. (Menopause (2004):
17beta-estradiol
vaginal tablet versus conjugated equine estrogen vaginal
cream to relieve menopausal atrophic vaginitis)
study also noted a higher number of women found the
tablet to be more acceptable than the cream.
It should also be noted that all forms of intravaginal
estrogen reduce the incidence of recurrent urinary
tract infection in postmenopausal women.
(2) Vaginal Moisturizers
There are several additional options for relief from
vaginal dryness. Several studies have demonstrated
improvement in vaginal symptoms as well as in vaginal
epithelium maturation with the use of the vaginal
moisturizer, Replens (Replens Vaginal Moisturizer,
from Parke-Davis), equivalent to that provided by
vaginal estrogen creams, with equivalent improvement
of vaginal itching, irritation, and dyspareunia (see
van der Laak, J Clin Pathol (2002): The
effect of Replens® on vaginal cytology in the
treatment of postmenopausal atrophy: cytomorphology
versus computerised cytometry; Bygdeman &
Swahn, Maturitas (1996): Replens
versus dienoestrol cream in the symptomatic treatment
of vaginal atrophy in postmenopausal women;
Nachtigall, Fertil Steril (1994): Comparative
study: Replens versus local estrogen in menopausal
women). Wilhite & O'Connell compared Replens
with the lubricant KY Jelly in a double-blind, randomized,
crossover trial (Pharmacotherapy (2001): Urogenital
Atrophy: Prevention and Treatment) and found that
Replens provided a longer duration of lubrication
as well as a lower vaginal pH, and was markedly preferred
by more women than KY Jelly. See also the review of
Pinkerton & santen (Endocr Rev (1999): Alternatives
to the Use of Estrogen in Postmenopausal Women);
and Loprinzi et al. (J Clin Oncol (1997): Phase
III randomized double-blind study to evaluate the
efficacy of a polycarbophil-based vaginal moisturizer
in women with breast cancer) examined the
efficacy of vaginal moisturizers specifically in breat
cancer populations, concluding that Replens substantially
ameliorates vaginal dryness and dyspareunia (pain
during intercourse) in breast cancer survivors, with
the bulk of the beneficial effects appeared within
the first 2 weeks of the first treatment and remained
constant thereafter. (See also Loprinzi & Barton,
J Natl Cancer Inst (2000): Estrogen
Deficiency: In Search of Symptom Control and Sexuality),
and J. Clin. Endocrinol. Metab (1998): Treatment
of Estrogen Deficiency Symptoms in Women Surviving
Breast Cancer)
Note that there is no evidence that vaginal lubricants
(like KY Kelly) have any long-term therapeutic effect
on vaginal atrophy or dryness, being limited in effectiveness
to decreasing immediate irritation during coital activity
(SOGC (Society of Obstetricians and Gynaecologists
of Canada), 2004: The
Detection and Management of Vaginal Atrophy).
(3) Tibolone
We have already in our discussion of tibolone above
noted the highly beneficial effect of tibolone on
vaginal lubrication and blood flow.
(4) Calcitriol (Vitamin D)
Yildirim et al. (Maturitas (2004): The
effects of postmenopausal Vitamin D treatment on vaginal
atrophy) demonstrated the efficacy of a Vitamin
D analogue, calcitriol (1,25-dihydroxy Vitamin D (calcitriol))
for relieving vaginal atrophy.
(5) Lifestyle Modification:
Coital Activity and Masturbation
It has been shown that continued regular vaginal coital
activity provides protection from urogenital atrophy,
it is hypothesized via increasing blood flow to the
pelvic organs (Leiblum et al., JAMA: Vaginal
atrophy in the postmenopausal woman: the importance
of
sexual activity and hormones). In addition,
masturbation also increases genital blood flow in
menopausal women and therefore
appears to assist in the maintenance of urogenital
health (Laan & Lunsen, Psychosom Obstet Gynecol
(1997): Hormones
and sexuality in postmenopausal women: a psychophysiological
study.
Note: Cranberry + Lingonberry Juice Concentrate for
UTI
Although a widely held view, the evidence (Cochrane
Review (2004): Cranberries
for preventing urinary tract infections) is
nonetheless inconclusive on whether the consumption
of cranberry juice significantly reduces the risk
of urinary tract infection. However, a recent clinical
trial (Kontiokari et al., BMJ (2001):
Randomised
trial of cranberry-lingonberry juice and Lactobacillus
GG drink for the prevention of urinary tract infections
in women) found that a cranberry / lingonberry
juice concentrate significantly reduced the risk of
urinary tract infection.
(6) Red Clover Isoflavones
(Promensil):
In the study cited above (Annual Meeting of the British
Menopause Society (Manchester, July 2003): Effects
of red clover isoflavones (Promensil) versus placebo
on uterine endometrium, vaginal maturation index and
the uterine artery in healthy postmenopausal women)
to the Annual Meeting of the British Menopause Society
(July 5, 2003), Woods and Whitehead evaluated the
efficacy and safety of Promensil (red clover isolflavones)
on endometrial thickness, uterine blood flow and (VMI)
vaginal maturation index, finding that Promensil effected
vaginal atrophy positively without increase in endometrial
thickness.
(7) Topical Vasoactive Drugs:
Alprostadil:
Alprostadil, a vasoactive prostaglandin agent, has
been used successfully in the treatment of male erectile
dysfunction, originally by inconvenient injection,
but now by topical cream/gel (Alprox) application
or TD (transdermal) patch. Topical application of
1 gram of a 0.2% alprostadil gel, has been suggested
on the basis of methodologically weak evidence from
two early uncontrolled studies for relief of certain
vaginal/clitoral symptoms of FSD (female sexual dysfunction)
(Becher et al., J Sex Marital Therap (2001): Clitoral
Hemodynamic Changes after a Topical Application of
Alprostadil, and Mitchell et al. (J Sex Marital
Therap (2001): Topical
Alprostadil in the Treatment of Female Sexual Arousal
Disorder: A Pilot Study. However, a later
controlled study by Padma-Natyhan et al. (J Sex Marital
Therap (2003): Efficacy
and safety of topical alprostadil cream for the treatment
of female sexual arousal disorder (FSAD): a double-blind,
multicenter, randomized, and placebo-controlled clinical
trial) demonstrated that responses of subjects
using the cream were not different from that of the
placebo cream.
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