Evidence-based Menopause Treatment Guidance - The State of the Art
Compiled by: Constantine Kaniklidis, medical researcher
[Breast Cancer Watch is a member of the Evidencewatch portal of evidence-based medicine sites]

Latest evidence-based guidance on menopause therapies, with critical commentaries and clinical practice recommendations. [last update: July. 1, 2010]  

Relief of Menopausal Vasomotor Symptoms: Hot Flashes / Vaginal Atrophy



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.

  • Femal Pollen Extract:
    Winter et al. (Climacteric (2005): Femal, a herbal remedy made from pollen extracts, reduces hot flushes and improves quality of life in menopausal women: a randomized, placebo-controlled, parallel study) found that the standardized pollen extract Femal (at 160mg. twice daily, from Sea-band Ltd.) significantly reduced hot flushes and certain other quality-of-life menopausal symptoms when compared to placebo (and in another double-blind, placebo-controlled, randomized, multicenter study reported by Gerhardsen et al. (Presented at the 6th Congress of the European Society of Gynecology (ESOG), Helsinki, Finland, June 2-4, 2005: Femal, a natural remedy based on two pollen extracts,reduces symptoms of PMS [pdf]) Femal was found to reduce major symptoms of PMS especially in patients reporting irritability, short fuse, anger or hostility as the most predominant symptoms).

  • Hops Extract:
    Heyerick et al. (Maturitas (2005): A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts) evaluated efficacy of a hop extract (100 or 250 µg)) enriched in 8-PN (8-prenylnaringenin, the phytoestrogen component of hops (Humulus lupulus L.)) on relief of vasomotor symptoms such as hot flashes and other menopausal discomforts, finding both does to exert significant favorable effects, with no advantage for the higher dose. Breast Cancer Watch notes however from our own research that 8-prenylnaringenin (8-PN), also called hopein, which belongs to the class of polyphenols, more specifically to the subclass of prenylflavonoids, has been confirmed independently as the most estrogenic constituent of hops (Overk et al., J. Agric. Food Chem (2005): Comparison of the in Vitro Estrogenic Activities of Compounds from Hops (Humulus lupulus) and Red Clover (Trifolium pratense)), raising concerns of adverse activity in the breast cancer setting, a matter not addressed in the Heyerick study. See also Rong et al. (Eur J Cell Biol (2005): 8-Prenylnaringenin, the phytoestrogen in hops and beer, upregulates the function of the E-cadherin/catenin complex in human mammary carcinoma cells) who found that 8-PN mimics the effects of 17-estradiol on MCF-7/6 cells; Zierau et al. (Planta Med (2002): Estrogenic Activity of the Phytoestrogens Naringenin, 6-(1,1-Dimethylallyl)naringenin and 8-Prenylnaringenin). However, Breast Cancer Watch further notes that findings from preclinical studies show other components of hops are known to be chemopreventive (C Gerhauser, Eur J Cancer (2005): Beer constituents as potential cancer chemopreventive agents) and Albini et al., FASEB J (2006): Mechanisms of the antiangiogenic activity by the hop flavonoid xanthohumol: NF-?B and Akt as targets), so the full clinical impact of hops components in the aggregate is not established, and we suggest caution given the well established tumorgenic activity of alcohol itself, this suggesting further that any net benefit from beer consumption may be more safely and prudently obtained from one of the many nonalcoholic beers that are currently available (O'Doul's, Kaliber, etc.).





  • Tibolone

    • Breast Cancer Watch Alert: LIFT Tibolone Study Halted: Increased Risk of Stroke

    • LIFT Tibolone Study Halted: Increased Risk of Stroke
      Breast Cancer Watch
      reports an early termination of the Organon LIFT study investigating tibolone efficacy on new vertebral fractures in elderly osteoporotic women under DSMB and Steering Committee rules. The interim findings reported an increased incidence of ischemic plus hemorrhagic events (strokes) in tibolone treatment group compared to the control group.

      The precise and full clinical implications however are not wholly clear:

      1. The study population was elderly osteoporotic women with a high risk of fracture, with the average age at baseline (study entry - recruitment began in 2001, and recruitment completed June 2003) of 68. Yet the vast majority of tibolone users average 10 years younger given typical deployment for vasomotor (climacteric) hot flashes. Indeed, Breast Cancer Watch notes that Organon scientists determined in 2004 that at least in the UK, tibolone was preferentially prescribed to women with an increased risk for breast and endometrial cancer (Wierik et al. Climacteric (2004): Clinical background of women prescribed tibolone or combined estrogen + progestogen therapies: a UK MediPlus study).

      2. The Organon Tibolone Clinical Study Database, comprised of more than 6500 women-years of tibolone use in women who are on average much younger than the elderly osteoporotic women included in the LIFT study, fails to suggest any significant increased risk of stroke.

      3. The study dose used in the LIFT study was 1.25 mg./daily, and indeed 1.25 mg also (as compared with 2.5 mg/daily) significantly decreases hot flashes, although the higher 2.5 mg tibolone dose is both faster in onset of action and with higher reductions in hot flash frequency and severity. However, it is important to note that the clinical trial database does not suggest that in younger postmenopausal women treated with either dose of tibolone, 2.5 mg nor 1.25 mg, there is any increased risk on stroke.

      4. It appears that the parameter with the most impact in the LIFT study's outcome regarding stroke is age, although this is also true for the placebo group. The fact that NO increases in incidence of VTE (venous thromboembolism) nor MI (myocardial infarction) are found with tibolone makes it more difficult to explain the mechanism by which tibolone increases the risk on stroke in these elderly women (I am indebted to Dr. Mirjam Mol-Arts, Livial Global Venture Teamleader and head of clinical projects in HRT at Organon, manufacturer of tibolone (Livial), for this clarification).

        Indeed, Breast Cancer Watch notes that in our own research, some studies have found tibolone (2.5 mg/daily) to be safe in postmenopausal patients with high risk factors in their history such as thromboembolic disorders, diabetes mellitus, hypertension, cardiovascular disease, pulmonary embolism, and stroke (see F. Szanto, Tibolone therapy in postmenopausal women with a history of many risk factors) over a 36-month period, a finding hard to reconcile with the LIFT results.

      5. Against the thrust of the LIFT study findings on stroke, tibolone as a six-month course (at 2.5 mg/daily) in postmenopausal women was found to counteract the increase of the intima media thickness (IMT) of the common carotid arteries (CCA), as determined by Anedda et al. (Hormone Res (2004): Observational Study on the Efficacy of Tibolone in Counteracting Early Carotid Atherosclerotic Lesions in Postmenopausal Women) and also by Erenus et al. (Fertil Steril (2002): Effect of tibolone treatment on intima-media thickness and the resistive indices of the carotid arteries), and this suggests an anti-atherosclerotic effect by tibolone, as it is well-established that increased CCA-IMT values are associated with a higher risk of long-term stroke recurrence (Tsivgoulis et al., Stroke (2006): Common Carotid Artery Intima-Media Thickness and the Risk of Stroke Recurrence). [Tibolone's effect on CRP (C-reactive protein), also a risk factor for stroke, is not wholly clear, as there have been inconsistent findings across studies.]

    § Some Guidance on Stroke Risk Reduction

    Breast Cancer Watch continues to investigate this issue and will post additional guidance as appropriate, but pending that advises that women currently using tibolone explore this matter candidly with their physicians. Breast Cancer Watch advises, however, for any women who elects to continue tibolone therapy that at the very least some basic proactive stroke-preventive measures be taken:



    • Tibolone: Overview of Activity & Benefits
      Tibolone is a new class of agent known as a STEAR (Selective Tissue Estrogenic Receptor Regulator), which appears to be exceptionally promising for the relief of menopausal symptoms, among several other beneficial actions. L. Speroff and TB Clarkson (Contemporary Ob/Gyn: Is tibolone a viable alternative to HT?) reviewed the literature and affirm the viability of tibolone ((derived from soybeans and yams, and already well-established for its ability to prevent bone loss) as an alternative to HRT, and this report furthermore found tibolone as effective as HRT in the relief of hot flashes and vaginal dryness, while significantly improving sexual response, all with an excellent side effect profile. More recently, Keneman, Speroff, and the International Tibolone Consensus Group (Maturitas (2005): Tibolone: Clinical recommendations and practical guidelines: A report of the International Tibolone Consensus Group) have concluded that as well as relieving vasomotor symptoms, tibolone shows positive effects on sexual well-being and mood, with improvement of vaginal atrophy and urogenital symptoms and that bone loss prevention was comparable to that of estrogen therapy (ET) and estrogen/progestogen therapy (EPT); similar conclusions were drawn in a recent review in Lancet by Hickey et al. (Lancet (2005): Treatment of menopausal symptoms: what shall we do now?) who concluded that tibolone is as effective as HRT and might also improve libido.

      Furthermore, tibolone exhibits several additional beneficial activities. It lowers estrogen breast tissue concentration, with no cell-proliferative activity, potentially protective in breast cancer. The ongoing LIBERATE (Livial Intervention following Breast cancer Efficacy, Recurrence And Tolerability Endpoints) trial (presenting first data at end of 2007) seeks to clarify this further, by studying menopausal symptom relief in postmenopausal women with a history of breast cancer, where traditional hormone therapies (estrogen / progesterone) are contraindicated, leaving these women without any approved treatment option for relief of menopausal symptoms like hot flashes and night sweats. (Other confirming studies have recently appeared, among them Langren et al. (Maturitas (2004)
      :
      Tibolone relieves climacteric symptoms in highly symptomatic women with at least seven hot flushes and sweats per day).

      In addition, Gulseren et al. (Aust N Z J Obstet Gynaecol (2005): Effects of tibolone on the quality of life, anxiety-depression levels and cognitive functions in natural menopause: An observational follow-up study)
      confirmed broad quality-of-life benefits with tibolone in the areas of anxiety and depression as well as in menopausal symptoms.

      Given the special problem of tamoxifen-induced hot flashes, Kroiss et al. (BJOG (2005): The effect of tibolone in postmenopausal women receiving tamoxifen after surgery for breast cancer: a randomised, double-blind, placebo-controlled trial) evaluated the effects of tibolone on climacteric symptoms, as well as on the endometrium and serum lipid/lipoproteins in postmenopausal women receiving tamoxifen after surgery for breast cancer. Their study found that tibolone prevented an increase in hot flushes, with a significant reduction in the severity of flushes with tibolone compared with placebo in postmenopausal women given tamoxifen following surgery for breast cancer, without untoward effects on the endometrium (established by endometrial biopsy of endometrial thickness and histology, and vaginal bleeding). This confirms the findings of an earlier small RCT by Bundred & Taylor (Maturitas (2004): Postmenopausal hormone therapy before and after breast cancer: clinical experiences) re the reduction in hot flashes and night sweats by tibolone in women with early breast cancer undergoing adjuvant tamoxifen treatment.

      Note: Although the authors conclude a beneficial effect of tibolone on serum lipid profile, on the basis of an observed significant decrease in triglycerides, Breast Cancer Watch notes that the benefit may be overstated, as there was also an unwanted significant decrease in HDL, so it cannot be concluded that the total cardiovascular impact is a net benefit.

      Note that some researchers identify tibolone more precisely as within a new class of SEEMs: Selective Estrogen Enzyme Modulators, agents showing an inhibitory effect on sulfatase and 17-hydroxysteroid dehydrogenase, or a stimulatory effect on sulfotransferase and consequently on the levels estradiol; that is, within a class of agents with a constellation of breast cancer-protective mechanisms. Breast Cancer Watch views this categorization as more clinically appropriate than th
      e broader STEAR (Selective Tissue Estrogenic Receptor Regulator) designation.

    • Issue of Tibolone and Endometrial Activity
      In the recent comprehensive review of tibolone cited above (L. Speroff and TB Clarkson (Contemporary Ob/Gyn: Is tibolone a viable alternative to HT?) the authors examined this issue of endometrial effects and concluded: "We can state with confidence that tibolone does not cause endometrial proliferation".

      However, one recent open, prospective, comparative study (Perez-Medina et al., Menopause: Tibolone and risk of endometrial polyps: a prospective, comparative study with hormone therapy) has found that tibolone significantly increased the risk of endometrial polyps. The import of this finding is not clear at present, and Breast Cancer Watch speculates that it may have been dose-dependent, as the study used 2.5mg/daily of tibolone (typical for menopausal symptom relief), although 1.25mg/daily is an alternate deployable regimen known to still have favorable anti-osteoporotic benefit.
      In this connection, the findings of Blok et al. ( Clin Endocrinol Metab (2003): Progestogenic effects of tibolone on human endometrial cancer cells) are suggestive: using a progesterone-responsive endometrial cancer cell line, it was discovered that one metabolite of tibolone displayed clear progestagenic effects on cell growth and gene regulation, but that another (3ß-OH-tibolone) had some minor, but significant, inhibitory effects on cell growth. It may be that the cumulative endometrial effect is neutral.

      And it should be noted that in any case, tibolone showed the least activity on endometrial polyp formation compared to two other regimens, conjugated estrogen + medroxyprogestorone, and estradiol + norethisterone, with no malignancy detected in any of the regimens (Oguz et al., Maturitas (2005): The role of hormone replacement therapy in endometrial polyp formation).

    • Breast Cancer Watch Commentary
      Given the concern of potential negative endometrial activity by tibolone when it is considered as an HRT alternative, Breast Cancer Watch has therefore conducted a comprehensive and systematic review of the literature on the endometrial effects of tibolone, current as of February 2005, to be updated as necessary if future research were to materially suggest changing our present conclusions; our findings are presented here:

      One the one hand, we have the findings of the Perez-Medina study cited above, and a case report by Yazigi et al. (Gynecol Oncol (2004): Carcinoma of the endometrium in patients treated with tibolone) of four cases of histologically diagnosed adenocarcinoma of the endometrium in women using tibolone. The authors however noted prudently that they do not suggest causality between the use of tibolone and the development of endometrial malignancy, only a limited observed association which "should alert physicians to thorough investigation in patients presenting with vaginal bleeding while on tibolone, despite the absence of endometrial thickness by sonogram".

      Against these limited findings, on the other hand, we have several well-controlled and carefully designed studies which collectively and strongly find against a significant negative impact of tibolone on endometrial health. Thus, in their RCT, Wender et al. (Menopause (2004): Endometrial assessment in women using tibolone or placebo: 1-year randomized trial and 2-year observational study) found that tibolone does not exert a stimulatory effect on the endometrium: (based on: unaltered endometrial thickness, atrophic appearance of most endometria on hysteroscopy, and endometrial histology classified as atrophic, hypotrophic with incipient secretion, or hypotrophic with weak proliferation (one case)), while showing itself to be effective in the treatment of climacteric symptoms; only 8.7% of the participants presented uterine bleeding during treatment. They concluded that "tibolone seems to be an effective option for the treatment of climacteric symptoms in postmenopausal women, especially in women who do not want to experience uterine bleeding again". This supports the earlier findings of Volker et al. (Climacteric (2001): Effects of tibolone on the endometrium) over a one- and two-year study that "in the majority of women (92%), the endometrium remained atrophic during 24 months of tibolone".

      Comparable findings exist for tibolone in the longer term, out to 10 years: Bruce et al., Climacteric (2004): Long-term effects of tibolone on the endometrium as assessed by bleeding episodes, transvaginal scan and endometrial biopsy) which found that although tibolone therapy led to high rates of amenorrhea after 10 years, there was minimal evidence of adverse effects on endometrial pathology.

      Similarly, Hudita et al. (Eur Rev Med Pharmacol SCI (2003): Efficacy and safety of oral tibolone 1.25 or 2.5 mg/day vs. placebo in postmenopausal women) took up a related issue: that although tibolone at usual doses of 2.5 mg/day in postmenopausal women improves climacteric complaints, without affecting endometrial thickness, the potentially similar efficacy, but better tolerability, of low dose tibolone (1.25 mg) needed to be clinically confirmed, which their study did indeed do. They found that although climacteric (hot flushes, sweating episodes, and vaginal dryness) symptoms were improved earlier in the group treated with tibolone 2.5 mg., both groups were similarly improved in degree by tibolone 1.25 and 2.5 mg. On the other hand, quality of sexual life was almost invariably improved by tibolone as compared to placebo, but in this case improvement surprisingly occurred earlier in the tibolone 1.25 mg group than in the higher dose group.

      And on the issue of concern here, endometrial thickness and breast density, these were not changed by tibolone treatment. It would thus appear from this study that the lower 1.25mg tibolone dose is indeed an effective and viable option for menopausal symptom treatment (and may be preferable on the factor of quality of sexual life, as it demonstrated more rapid onset).

      Similarly, Kurtay et al. (J Reprod Med (2004): Transvaginal ultrasonographic assessment of the endometrium in asymptomatic, postmenopausal women using different HRT regimens containing tibolone or estrogen) found that changes in endometrial thickness were not statistically significant in patients taking tibolone, and that endometrial thickness with tibolone closely mimics the naturally atrophic postmenopausal state, making tibolone a first-line choice for those postmenopausal women with concerns about HRT.

      Breast Cancer Watch finds therefore that the balance of evidence demonstrates the efficacy and safety of tibolone in the treatment of menopausal vasomotor symptoms, in addition to its exhibiting osteoprotective effects, with no compelling evidence of negative impact on either endometrial or breast tissue; indeed, there is some strong suggestion that tibolone may be protective in the endometrium and in breast disorders.

    • The Issue of Breast Cell Proliferation
      In the so-called MWS (Million Women Study) conducted in Britain (Beral et al., Lancet:
      Breast cancer and hormone-replacement therapy in the Million Women Study) it was found that the incidence of breast cancer was significantly increased for current users of preparations containing estrogen only, estrogen-progestagen, and tibolone, with the magnitude of the associated risk substantially greater for estrogen-progestagen than for the other types of HRT. This appears to be the first report of any association between tibolone and breast cancer.

      Given the seriousness of this finding and its impact on tibolone as a viable option for menopausal symptom treatment, Breast Cancer Watch has therefore conducted a comprehensive and systematic review of the literature on the issue of tibolone and breast cancer risk, current as of January 2006, to be updated as necessary if future research were to materially suggest changing our present conclusions.

    • Breast Cancer Watch Review
      The first point to note is the design of MWS: it investigated the effects of hormone replacement therapy (HRT) on the health of women, aged between 50 and 64 years, attending the NHS Breast Screening Programme (NHSBSP) between 1996 and 2001 (1,084,110 women) who were invited to attend UK breast screening units and complete a questionnaire about their lifestyle, socioeconomic background, reproductive and medical history and HRT use. The MWS Collaborators published their findings - based on this questionnaire data - on the effect of HRT on breast cancer incidence and mortality in August 2003. Hence MWS is not a randomized trial, only an observational, questionnaire-based study. Furthermore, it is in our opinion certainly possible if not probable that women at higher risk of breast cancer were more likely to opt for tibolone treatment, something that would bias the findings and compromise the conclusions' validity.

      Indeed, the authors themselves have previously noted (BJOG (2002): Patterns of use of hormone replacement therapy in one million women in Britain, 1996–2000) that studies such as MWS where patients elect their own treatment are subject to bias, and they consequently advised caution in the interpretation of such findings, advice not manifestly followed by the same authors in the later MWS study under consideration. We return to the methodological problems and suboptimal observational design of the MWS study again and further, below. But let us now examine the weight of evidence.

      Kutlu et al. (Maturitas (2004): Mammographic breast density changes after 1 year of tibolone use) studied the effects of tibolone on mammographic density, concluding that as a tissue-specific steroid, tibolone not only was devoid of an estrogenic effect on breast cells, but further that "it might limit, even reverse breast density increase, especially in postmenopausal women with high breast density".
      This is consonant with the comparable findings of Bisanti et al. (Minerva Ginecol (2004): Effects of hormonal replacement therapy on breast density in postmenopausal women) to wit, that tibolone does not significantly affect breast density, making it a preferable therapy for postmenopausal women, including women with a familiar history of breast cancer, and those with significant breast density; see also the confirming study of Boutet et al. (J Radiol (2004): Menopausal hormonal therapies: impact on mammographic breast density) finding no negative impact on mammographic density of either tibolone nor raloxifene. This is recently further confirmed by Conner et al. (Climacteric (2004): A comparative study of breast cell proliferation during hormone replacement therapy: effects of tibolone and continuous combined estrogen-progestogen treatment) where it was concluded that "tibolone seems to have little influence on breast cell proliferation in postmenopausal women".

      In the somewhat longer-term, Pantidou et al. in their ongoing study (Eur J Gynaecol Onco (2004): Mammographic changes during postmenopausal hormonal replacement therapy with tibolone) have reported to-date results that at least tibolone therapy of less than 5 years has positive effects on climacteric disorders and does not cause adverse breast changes (dysplasia or cancer).

      Even more noteworthy are the findings of Valdivia et al. (Fertil Steril (2004): Effects of tibolone and continuous combined hormone therapy on mammographic breast density and breast histochemical markers in postmenopausal women) where one-year treatment with tibolone induced a decrease in breast density, along with a reduction in proliferation and a stimulation of apoptosis, in contrast with with CEE-MPA (CEE = conjugated equine estrogens, MPA = medroxyprogesterone acetate), which induced an increase in breast density, with stimulation of proliferation and inhibition of apoptosis. Thus tibolone treatment showed strong antiproliferative activity coupled with other positive molecular and genetic activity, favorable news given that one of the most common reasons for withdrawing from long-term use of conventional hormone therapy is fear of breast cancer. And in - and subject to the methodological limitations of - a recent prospective, open, nonrandomized study (Dimitrakakis et al., Climacteric (2005): Clinical effects of tibolone in postmenopausal women after 5 years of tamoxifen therapy for breast cancer), it was found that cancer recurrence rate in the tibolone group was comparable to that of untreated controls, with no breast-related adverse effects, and overall safety and tolerance similar to those of the general population of postmenopausal women treated with tibolone.

      Indeed, there are direct findings to suggest that tibolone may exhibit a protective effect in regards to breast cancer. Pasqualini (Maturitas (2003): Differential effects of progestins on breast tissue enzymes) found that various progestins as well as tibolone and its metabolites have been shown to inhibit estrone sulfatase. The importance of estrone sulfatase inhibition is that the sulfatase pathway is one of the two principal pathways implicated in the final steps of estradiol formation in breast cancer tissue (the other is the aromatase pathway that transforms androgens into estrogens). Tibolone and these progestins also inhibit 17-hydroxysteroid dehydrogenase (17-HSD); this is important because the final step in the local biosynthesis of estradiol from circulating precursors is the conversion of weak estrone to potent biologically active estradiol via reductive 17-HSD type 1 activity. Furthermore, some progestins and tibolone can also stimulate sulfotransferase activity (steroid sulfotransferases, which convert estrogens into their sulfates, are present in breast cancer tissues). Thus, although one well-known way of of blocking estradiol effects in breast cancer is to use antiestrogens, which act by binding to the estrogen receptor (ER), a different option is to use anti-enzymes as estradiol-blockers (anti-sulfatase, anti-aromatase, or anti-17-HSD). In sum, the author notes therefore that tibolone may indeed provide a new option for the treatment of breast cancer.

      This is in substantial agreement with the animal study of HJ Kloosterboer (Maturitas (2004): Tissue-selectivity: the mechanism of action of tibolone) who sought to detangle tibolone's tissue-selective action. Re breast tissue, Kloosterboer found that such tissue is not stimulated by tibolone, as it is with estrogen plus progestogen, because of tibolone's (and its metabolites) inhibition of sulphatase and 17-HSD type I and stimulation of sulphotransferase and 17-HSD type II, yielding a combined effect of preventing conversion to active estrogens. In addition, by inhibiting proliferation and stimulating apoptosis, tibolone favorably affects cellular homeostasis in the breast. Moreover, tibolone is effective in bone loss prevention and climacteric symptoms treatment without stimulation of the endometrium, as it appears that the effects on bone, brain and the vagina are accurately explained by the tibolone's estrogenic activity, without such estrogenic activity being expressed in the endometrium, largely due the action of a highly stable progestogenic metabolite, coupled with its estrogen-inactivating enzyme effect on the sulphatase (inhibition)–sulphotransferase (stimulation) system. Finally, the estrogenic metabolites of tibolone have direct favorable effects on the cardiovascular system. In this sense, tibolone can be characterized as a selective estrogen activity regulator, as it appears to regulate estrogenic activity in the various tissues by influencing the estrogenic compound availability for the estradiol receptor in a tissue-selective manner.

      Postmenopausal women (n = 102) with early-stage ER+ primary breast cancer received tibolone or placebo for 14 days in an exploratory, double-blind, randomized trial (STEM carcinoma tissue). Serum metabolite patterns of estradiol and tibolone are different from those in tissues and are compatible with neutral effects of tibolone on breast Ki67 expression. [Kloosterboer HJ, Löfgren L, von Schoulz E, von Schoultz B, Verheul HA. Estrogen and tibolone metabolite levels in blood and breast tissue of postmenopausal women recently diagnosed with early-stage breast cancer and treated with tibolone or placebo for 14 days. Reprod Sci. 2007 Feb;14(2):151-9; see also Kloosterboer HJ. Historische Meilensteine bei der Entwicklung von Tibolon (Livial (R)). Journal für Gynäkologische Endokrinologie 2008; 2 (1) (Ausgabe für Schweiz): 38-46 [pdf]].

      Lucie Opatrny at McGill University and coresearchers found that breast cancer risk varied with the formulation and preparation of HRT, with as expected opposed estrogens (progesterone-estrogen) in oral form being associated with an increased risk (and increasing with use), while tibolone, transdermal opposed estrogens and unopposed estrogens not associated with risk increase [Opatrny L, Dell'Aniello S, Assouline S, Suissa S. Hormone replacement therapy use and variations in the risk of breast cancer. BJOG 2008 Feb; 115(2):169-75; see also Wang PH, Cheng MH, Chao HT, Chao KC. Effects of tibolone on the breast of postmenopausal women. Taiwan J Obstet Gynecol 2007 Jun; 46(2):121-6].

      It has been confirmed across several numerous that although tibolone exerts estrogenic effects on bone, brain, and the urogenital system (via its hydroxymetabolites), it appears not to stimulate either the endometrium or to increase breast tissue proliferation, this absence of estrogenic activity likely secondary to its inhibition of sulfatase and the stimulation of sulfotransferase in breast tissue, with inhibition of the sulfatase enzyme and promotion of apoptosis in normal as well as breast cancer cells, thus suggesting local antiestrogenic activity, and furthermore tibolone users do not develop an increase in mammographic density, as demonstrated by [Bundred NJ, Turner LE. Postmenopausal hormone therapy before and after breast cancer: clinical experiences. Maturitas 2004 Sep 24; 49(1):S22-31]. Dowsett et al. (15) have recently shown that the nuclear antigen Ki-67, which is expressed in proliferating cells, is an appropriate end point in neoadjuvant models of response to long-term endocrine therapies.

      Ernst Kubista Medical University of Vienna and colleagues have presented the results of the double-blind, randomized, placebo-controlled pilot STEM Trial (Study of Tibolone Effects on Mamma carcinoma tissue) investigating the tissue-specific effects, particularly tissue proliferation, of 2.5 mg tibolone on breast cancer in postmenopausal women () [Kubista E, Planellas Gomez JV, et al. Effect of Tibolone on Breast Cancer Cell Proliferation in Postmenopausal ER+ Patients: Results from STEM Trial. Clin Cancer Res 2007 Jul 15; 13(14):4185-90], which found that tibolone given for 14 days at 2.5 mg/d had no significant effect on tumor cell proliferation (as per the Ki-67 proliferation biomarker) in ER+ breast tumors.As to tibolone's positive impact on bone health, this has been confirmed over numerous studies, and most recently also in a head-to-head comparison with raloxifene (Evista) by Pierre Delmas at the University of Lyons and coresearchers [Delmas PD, Davis SR, Hensen J, Adami S, van Os S, Nijland EA. Effects of tibolone and raloxifene on bone mineral density in osteopenic postmenopausal women. Osteoporos Int 2008 Feb 7] who found that tibolone at 1.25 mg/day for 2 years in older women prevented postmenopausal bone loss and produced a larger increase of BMD both at the lumbar spine and hip than raloxifene.
      Finally, as to positive effects on sexual function, Filiz Cayan and colleagues at the University of Mersin School of Medicine (Turkey) prospectively evaluated the effects of hormone therapy (HT) regimens, oral and vaginal estradiol, estradiol + drospirenone, and tibolone, on sexual function in healthy postmenopausal women, finding the highest improvement in orgasm achieved in the tibolone group [Cayan F, Dilek U, Pata O, Dilek S. Comparison of the Effects of Hormone Therapy Regimens, Oral and Vaginal Estradiol, Estradiol + Drospirenone and Tibolone, on Sexual Function in Healthy Postmenopausal Women. J Sex Med 2007 Oct 24], also confirmed by Esme Nijland at the University Hospital Groningen and coresearchers (Nijland EA, Schultz WC, Davis SR. Effects of tibolone and raloxifene on health-related quality of life and sexual function. Maturitas 2007 Sep 14) who found that in older postmenopausal women, tibolone therapy was associated with a trend towards improvement in sexuality and QoL when compared to raloxifene (Evista).

      In sum, Breast Cancer Watch finds the balance of the evidence to be against the findings of the MWS, and to suggest (1) that tibolone does not exhibit significant negative activity on either breast cell proliferation or density, and (2) that tibolone appears to exhibit at least some significant protective activity in breast cell neoplasia / carcinoma that may ultimately, pending confirmation in future trials, establish a role for tibolone in breast cancer treatment and prevention.

    • Breast Cancer Watch Criticism of MWS
      We have already noted above that the MWS is founded on suboptimal observational design, in sharp contrast to the placebo-controlled ("gold-standard") RCT methodological foundation of the WHI (Women's Health Initiative) study. In addition, and for the reasons given below, Breast Cancer Watch finds the conclusions of the MWS study regarding the association of tibolone and breast cancer risk to be untenable, against the weight of the evidence, and therefore in error.

      (1) As to methodological problems, first consider that the two studies (WHI and MWS) are in conflict as to the degree of risk conferred with combined and unopposed therapies. The WHI investigators reported a hazard ratio for invasive and in situ cancer of 1.24 after 5.6 years of follow up in women on continuous combined HRT (i.e. conjugated equine estrogens, CEE, 0.625 mg plus daily medroxyprogesterone acetate, MPA, 2.5 mg), which translates to a real risk increase of 24%. But the unopposed estrogen arm (i.e. CEE 0.625 mg) of the WHI study is continuing following an interim analysis (performed after 5.2 years of follow-up) as there has not emerged any evidence to date of excessive of breast cancer events. Yet the observational MWS study claims to have found a 100% risk increase for combined HRT, and so appears to have seriously overestimated potential breast cancer risk.

      (2) MWS further finds increase in breast cancer risk with less than one year’s exposure to combined HRT, directly in conflict with the WHI study where no increase in breast cancer risk emerged until 3 years after randomization.

      (3) Given that in the MWS study, the follow-up for breast cancer diagnosis was slightly over 2.5 years, it is highly probable that these were preexistent breast cancers at the start point of the observational period. (Indeed, the average time interval between recruitment and diagnosis of breast cancer was only approximately 1.2 years). But on the best oncological data and evidence, therefore, these tumors must be assumed to have been existent at baseline, and were somehow simply not captured by the recruitment mammography.


      (4) The MWS counter-intuitively found that premenopausal women exhibited statistically significant greater risk of breast cancer than never users of hormone therapy, whether pre- or post-menopausal, in direct conflict with the well-established fact of increased risk of breast cancer with age.

      (5) The MWS results concerning tibolone are against the evidence: in animal breast cancer models, tibolone invariably exerts protective effects, indeed apparently to the same degree as tamoxifen, despite the fact that, tibolone is not truly antiestrogenic nor an aromatase inhibitor, explainable as we noted above by enzyme effects (sulfatase and 17b-hydroxysteroid dehydrogenase inhibition, an sulfotransferase stimulation to increase the production of inactive sulfates). In addition, tibolone increases cellular differentiation while stimulating apoptosis (see all the studies cited in our main tibolone coverage of this report, above). But in contrast to postmenopausal hormone therapy which increases breast density on mammography, tibolone does not increase breast density, and exhibits significantly less mastalgia than estrogen treatment, consequent to its favorable effects on the breast tissue enzymes implicated in local estrogen production.

      (6) Contrary to the MWS findings, the estrogen only arm of the WHI clinical trial has discovered no significant breast cancer increase, even with an average follow-up that has now reached some 7 years, and given the RCT status of the WHI study, the observational MWS findings must be presumed in error.

      (7) MWS found tibolone to have the same risk for breast cancer as unopposed estrogen. But the WHI study established that estrogen alone does not increase breast cancer risk, so it must be presumed highly improbable that tibolone can increase breast cancer risk.

      (8) From Organon-compiled statistics, the incidence of breast cancer among participants in their phase III and phase IV studies did not achieve statistical significance compared to placebo, and therefore the wholly contradictory MWS results are unaccountable.

      (9) The best evidence suggests that HRT may be more accurately construed as a growth promoter for breast cancer, not as a true causative agent of new breast cancer, and it is not settled to date whether bringing out preexisting breast cancers may not ultimately be not wholly negative; indeed, it may be that HRT may primarily promote or facilitate the diagnosis of preexisting tumors.


    • Tibolone Drug Insert
      See the Drug Insert for detailed information on contraindications, warnings, side effects and special precautions, and drug interactions.




    • (new) Tibolone and Breast Cancer: Breast Cancer Watch Findings
      As we have noted above, tibolone exerts estrogenic activity on brain, vagina and bone without stimulation of breast and endometrium, and given that this selective activity depends on the specific tissue context, it has been cutomarily classified as a selective tissue estrogenic activity regulator (SERM). As to the breast, tibolone and its metabolites stimulate the formation of inactive estradiol sulfate and estrone sulfate by activation of sulfotransferase, and inhibition of sulfatase. To date, breast safety studies have shown that tibolone inhibits the growth of tumors in a DMBA model, while in breast cell lines, tibolone inhibits sulphatase activity, increases apoptosis and decrease cell proliferation (Kloosterboaer, J Steroid Biochem Mol Biol (2001): Tibolone: a steroid with a tissue-specific mode of action), and its pro-apoptotic effects appear at least partially mediated by a decreased expression of the anti-apoptotic proteins bcl-2 and bcl-xL (Anne Gompel et al., Fertil Steril (2002): In vitro studies of tibolone in breast cells).

      The evidence base shows that in breast tissue tibolone reduces bioactive estrogen tissue levels, as well as in human breast cancer cells (Morris Notelovitz, Medscape General Medicine, 9(1):2 (2007): Postmenopausal Tibolone Therapy: Biologic Principles and Applied Clinical Practice, and JR Pasquualini & GS Chetrite, J Steroid Biochem Mol Biol (1999): Estrone sulfatase versus estrone sulfotransferase in human breast cancer: potential clinical applications, who concluded in this study that tibolone inhibits local sulfatase activity within the breast and may thereby reduce the formation of biologically active estrogenic compounds), via these major pathways:

      (1) inhibition of the sulfatase conversion of estrone sulfate to estrone(Peter JG van de Ven at the University Medical Center Utrecht, and colleagues, J Steroid Biochem Mol Biol (2002): Effect of tibolone (Org OD14) and its metabolites on aromatase and estrone sulfatase activity in human breast adipose stromal cells and in MCF-7 and T47D breast cancer cells who concluded in this study that because tibolone and its metabolites inhibit sulfatase activity, and because tibolone only increases aromatase activity at high concentrations, the effects of tibolone on the breast are probably safe);

      (2) the reduction of 17beta-HSD type 1 mediated metabolism of estrone to estradiol, where it should be note that 17beta-HSD type 1 oxidizes estradiol to the less active estrone, and to inactive estrone sulfate via estrone sulfotransferase (see (van de Ven et al., above);

      (3) the stimulation of sulfotransferase, which reverses the conversion of estrone sulfate to estrone (Gérard Chetrite and colleagues at the Institut de Puériculture, Anticancer Res (1999): Effect of Org OD14 (LIVIAL) and its metabolites on human estrogen sulphotransferase activity in the hormone-dependent MCF-7 and T-47D, and the hormone-independent MDA-MB-231, breast cancer cell lines, who concluded in this study that the stimulatory effect provoked at low doses by tibolone and its metabolites on the estrogen sulphotransferase which is involved in the biosynthesis of inactive estrogen sulphates in estrogen-dependent breast cancer cells, can contribute to the protection of breast tissue in postmenopausal women with hormone replacement therapy) - and furthermore, tibolone and its delta4-isomer upregulates 17beta-HSD type 2 activity and the conversion of estradiol back to estrone;

      and this tibolone-induced sulfatase activity decrease being tissue specific, with most (70%-90%) occuring in breast cancer cells, but none in osteoblast cells (Marcel de Gooyer, Mol Cell Endocrinol (2001): Tibolone: a compound with tissue specific inhibitory effects on sulfatase who concluded in this study that the tissue specific inhibition pattern of sulfatase activity by tibolone and its metabolites suggest tibolone as protective against the development of mammary carcinomas, while retaining favorable estrogenic effects on bone). Furthermore, tibolone has minimal influence on breast cell proliferation, and shows in addition minimal (2%-6%) increase in post therapy mammographic density (Eva Lundstrom and colleagues at the Karolinska Hospital, Sweden, Am J Obstet Gynecol (2002): Effects of tibolone and continuous combined hormone replacement therapy on mammographic breast density who concluded in this prospective randomized study that, in contrast to estrogen/progestogen treatment, tibolone exerted little stimulation of breast tissue, and that treatment with tibolone did not differ from that with placebo).

      In addition, tibolone and its 3ß-OH metabolite demonstrate an anti-invasive effect on MCF-7/6 and T47-D breast cancer cell lines in vitro, with this anti-invasive activity is being correlated with a decreased release of pro-MMP-9 in the medium, and with any effect on cell–cell adhesion or motility (BW Vanhoecke et al, Maturitas (2006): Tibolone and its metabolites inhibit invasion of human mammary carcinoma cells in vitro), nor it would appear with any effect on angiogeneis (FE Frankeene et al., J Clin Oncol (2006): Effect of tibolone on tumor angiogenesis parameters in short-term treated women), and Bindumalini Raobaikady and colleagues (Steroids (2006): Lack of aromatisation of the 3-keto-4-ene metabolite of tibolone to an estrogenic derivative) had previously found that the 7a-methyl norethisterone metabolite of tibolone does not undergo aromatisation to an estrogenic derivative (ethinylestradiol).

      Finally, in their recent small retrospective study, Michalis Goutzioulis and colleagues at the Aristotle University of Thessaloniki (J Obstet Gunaecol Res (2007): Tibolone therapy in breast cancer survivors: A retrospective study) investigated the relationship between tibolone therapy and recurrence or mortality in breast cancer survivors, it appears that tibolone is not associated with a negative impact on breast cancer outcome when given to breast cancer survivors for relief of menopausal symptoms (mean duration of use 37.1 months).

    • Our Conclusions on the Safety of Tibolone in Breast Cancer
      From these above-cited studies, Breast Cancer Watch concludes that the weight of the evidence supports the lack of adverse impact, breast-estrogenic or otherwise, of tibolone on breast cancer initiation or progression, and supports breast anti-estrogenic, anti-proliferative, pro-apoptopic,and anti-invasive activity, and hence in its overal effect, is protective against the development of breast carcinomas, while retaining powerful beneficial effects on vasomotor symptomology and bone health.

    • The LIBERATE Trial: Case Not Proven

      The LIBERATE (Livial Intervention following Breast cancer: Efficacy, Recurrence, And Tolerability Endpoints) trial (Kenemans et al., Lancet Oncol 2009) reported an augmented risk in the subgroup of patients with hormonal-dependent primary breast cancers using tibolone 2.5mg/d., but  there are some significant methodological issues which compromise the power to  support this conclusion: (1) there is an issue as to adherence to adjuvant endocrine therapy, given that in the per-protocol analysis subjects were excluded if they were found to be non-compliant to tibolone administration but not to tamoxifen or aromatase inhibitor (AI) therapy, a confounding given that subjects not adherent to TAM or AI therapy represent suboptimally treated women with a consequent expectation of unfavorable outcome, a serious if  not fatal bias for the LIBERATE  trial; surely the investigators should have appreciated that any non-adherence to adjuvant treatment in the tibolone group would tend to increase the recurrence rate and thus artificially accentuate the difference between the two arms. (2) comparable defect can be seen in the trial's surprising allowance of use of phytoestrogens (soy) or other unknown and unspecified medication that was neither controlled nor registered, since clearly the potential exists for allowance of an outcome-adverse agent, influencing the final recurrence rate. (3) in the hormone-dependant breast cancer population, tibolone can not be conceived as monotherapy as in fact it was added to endocrine therapy, introducing an unknown entity, that of the TAM/Tibolone or AI/Tibolone complex, with uncontrolled pharmacokinetics and unpredictable results in breast or other target tissues (and according to LIBERATE trial findings, tibolone would appear to counteract the preventive effect of tamoxifen).  (3) The expected recurrence rate in LIBERATE trial was 15%, reached in the tibolone group (15.2%) in contrast to the relapse rate of 10.7% for women in the control group, considerably less than expected, and given that  breast cancer survivors experiencing menopausal symptoms would have a low estrogen profile, that entails a low risk for recurrence, and this cannot be extrapolated to all or other subgroups of breast cancer survivors.  (4) There is an inconsistent and unexplainable phenomenon observed, that the subgroup of patients with a poorer prognosis of ER-negative tumors showed no statistical significant difference in recurrence between the tibolone and placebo arms, and in this case this constitutes a tibolone monotherapy cohort, but here the results indicate that tibolone as monotherapy did not increase the relapse rate and hence not be considered unsafe, an issue wholly unnoted and unaddressed in the trial.  (5) As I  have  elsewhere noted, other  studies of tibolone monotherapy in breast cancer survivors who completed their 5-years adjuvant  endocrine therapy resulted in no increase in breast cancer relapse of any kind (Dimitrakakis et al., Climacteric 2005; and in the LIFT trial, tibolone use in fact  substantially decreased breast cancer risk). (6) The LIBERATE trial investigators' argument that tibolone may induce a more aggressive outcome consequent to its expressing different actions within the cancer tissue is unconvincing: cancer tissue had been surgically removed, so no intratumoral metabolic action would be  expected. Thus, it is not established for the LIBERATE trial that tibolone alone, absent concurrent oncotherapy, is unsafe.


  • Treatment of Vaginal Atrophy / Dryness [Note: This section is in the process of  extensive update, pending  posting]
    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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