Suzanne Banuvar

Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial.

Objective: The aim of this study was to evaluate the safety and efficacy of black cohosh and red clover compared with placebo for the relief of menopausal vasomotor symptoms. Methods: This study was a randomized, four-arm, double-blind clinical trial of standardized black cohosh, red clover, placebo, and 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (CEE/MPA; n = 89). Primary outcome measures were reduction in vasomotor symptoms (hot flashes and night sweats) by black cohosh and red clover compared with placebo; secondary outcomes included safety evaluation, reduction of somatic symptoms, relief of sexual dysfunction, and overall improvement in quality of life. Results: Reductions in number of vasomotor symptoms after a 12-month intervention were as follows: black cohosh (34%), red clover (57%), placebo (63%), and CEE/MPA (94%), with only CEE/MPA differing significantly from placebo. Black cohosh and red clover did not significantly reduce the frequency of vasomotor symptoms as compared with placebo. Secondary measures indicated that both botanicals were safe as administered. In general, there were no improvements in other menopausal symptoms. Conclusions: Compared with placebo, black cohosh and red clover did not reduce the number of vasomotor symptoms. Safety monitoring indicated that chemically and biologically standardized extracts of black cohosh and red clover were safe during daily administration for 12 months.

Objective hot flashes are negatively related to verbal memory performance in midlife women.

Objective: To test the hypothesis that hot flashes specifically relate to verbal memory performance by examining the relationship between objective hot flashes and cognitive test performance in women with moderate to severe vasomotor symptoms. Design: In an observational study, 29 midlife women (mean age, 53 y) with moderate to severe hot flashes provided measures of objective hot flashes with an ambulatory hot flash monitor, subjective hot flashes with a diary and questionnaire, and objective measures of verbal memory and other cognitive functions with standardized neuropsychological tests. Results: The mean number of objective hot flashes was 19.5 per day (range, 6 to 35), including 15.3 (range, 6 to 35) during waking hours and 4.2 (range, 0 to 9) during sleep. The mean sensitivity (ie, subjective detection of objectively measured hot flashes) was 60%. Regression analyses revealed that total number of objective hot flashes, sleep duration, and verbal knowledge were significant predictors of delayed verbal memory. Verbal fluency correlated positively with objective daytime hot flashes. Hot flashes did not predict performance on any of the other secondary cognitive measures (ie, attention, working memory, visual memory), although poor sleep predicted worse performance on several outcome measures. Conclusions: Highly symptomatic women underreport the number of objective hot flashes that they experience by 43%. Verbal memory performance relates significantly to the objective number of hot flashes women experience but not to the number of hot flashes that they report. These findings suggest that physiological factors related to hot flashes, rather than psychological factors, predict poorer verbal memory function.

Clinical studies of red clover (Trifolium pratense) dietary supplements in menopause: a literature review

Red clover (Trifolium pratense L., Fabaceae) botanical dietary supplements have received much attention recently for their potential use in the treatment of menopause symptoms, maintenance/improvement of bone and cardiovascular health, and reported benign effects on the breast and endometrium. Literature searches of four computerized databases were run to identify clinical studies of red clover botanical dietary supplements. The manufacturer of the red clover products used in the majority of the studies was contacted for unpublished information and/or clarification regarding the chemical content of their products. Red clover studies were reviewed that pertained to women’s health or menopause. Clinical evidence is presently lacking to support the efficacy of semipurified red clover isoflavone extracts for alleviation of climacteric vasomotor symptoms or reduction of low-density lipoprotein levels in the blood. Furthermore, the safety of use of red clover isoflavone supplements in patients with breast or endometrial cancer has not been established. Limited evidence suggests possible efficacy in maintenance of bone health and improvement of arterial compliance, a risk factor for atherosclerosis. This literature review covers red clover botanical dietary supplement clinical studies having a possible impact on the health care of mature and menopausal women, and provides historical perspective regarding the traditional uses of red clover.

Effects of botanicals and combined hormone therapy on cognition in postmenopausal women.

Objective: The aim of this study was to characterize the effects of red clover, black cohosh, and combined hormone therapy on cognitive function in comparison to placebo in women with moderate to severe vasomotor symptoms. Methods: In a phase II randomized, double-blind, placebo-controlled study, 66 midlife women (of 89 from a parent study; mean age, 53 y) with 35 or more weekly hot flashes were randomized to receive red clover (120 mg), black cohosh (128 mg), 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (CEE/MPA), or placebo. Participants completed measures of verbal memory (primary outcome) and other cognitive measures (secondary outcomes) before and during the 12th treatment month. A subset of 19 women completed objective, physiological measures of hot flashes using ambulatory skin conductance monitors. Results: Neither of the botanical treatments had an impact on any cognitive measure. Compared with placebo, CEE/MPA led to a greater decline in verbal learning (one of five verbal memory measures). This effect just missed statistical significance (P = 0.057) in unadjusted analyses but reached significance (P = 0.02) after adjusting for vasomotor symptoms. Neither of the botanical treatment groups showed a change in verbal memory that differed from the placebo group (Ps > 0.28), even after controlling for improvements in hot flashes. In secondary outcomes, CEE/MPA led to a decrease in immediate digit recall and an improvement in letter fluency. Only CEE/MPA significantly reduced objective hot flashes. Conclusions: Results indicate that a red clover (phytoestrogen) supplement or black cohosh has no effects on cognitive function. CEE/MPA reduces objective hot flashes but worsens some aspects of verbal memory.

Pharmacokinetics of Prenylated Hop Phenols in Women Following Oral Administration of a Standardized Extract of Hops

SCOPE Women seeking alternatives to hormone-replacement therapy for menopausal symptoms often try botanical dietary supplements containing extracts of hops (Humulus lupulus L.). Hops contain 8-prenylnaringenin (8-PN), a potent phytoestrogen, the related flavanones 6-prenylnaringenin and isoxanthohumol (IX), and the prenylated chalcone xanthohumol (XN). METHODS AND RESULTS After chemically and biologically standardizing an extract of spent hops to these marker compounds, an escalating dose study was carried out in menopausal women to evaluate safety and pharmacokinetics. 8-PN, 6-prenylnaringenin, IX, and XN, sex hormones, and prothrombin time were determined in blood samples and/or 24 h urine samples. There was no effect on sex hormones or blood clotting. The maximum serum concentrations of the prenylated phenols were dose-dependent and were reached from 2 to 7 h, indicating slow absorption. The marker compounds formed glucuronides that were found in serum and urine. Secondary peaks at 5 h in the serum concentration-time curves indicated enterohepatic recirculation. The serum concentration-time curves indicated demethylation of IX to form 8-PN and cyclization of XN to IX. Slow absorption and enterohepatic recirculation contributed to half-lives exceeding 20 h. CONCLUSION This human study indicated long half-lives of the estrogenic and proestrogenic prenylated phenols in hops but no acute toxicity.

Effects of stellate ganglion block on vasomotor symptoms: findings from a randomized controlled clinical trial in postmenopausal women.

ObjectiveUncontrolled intervention studies, including studies involving breast cancer survivors, have demonstrated improvements in vasomotor symptoms (VMS) after stellate ganglion blockade (SGB) with a local anesthetic. This study presents the first randomized sham-controlled trial of SGB for the treatment of VMS. MethodsParticipants included 40 postmenopausal women, aged 30 to 70 years, with moderate to severe VMS. The study was a randomized sham-controlled trial comparing the effects of SGB versus sham injection on the frequencies of total and moderate to severe VMS, as measured by daily diaries. Image-guided SGB was performed with 5 mL of 0.5% bupivacaine. Sham injection of saline was performed in subcutaneous tissues in the neck. VMS were recorded at baseline and for 6 months thereafter. Objective VMS were recorded using ambulatory sternal skin conductance monitoring during a 24-hour period at baseline and on 3-month follow-up. ResultsThere were no significant group differences in overall VMS frequency, but the frequency of moderate to very severe VMS was reduced more in the active group compared with the sham treatment group (event rate ratio, 0.50; 95% CI, 0.35-0.71; P < 0.001). The frequency of objective VMS was also reduced to a greater degree in the SGB group than in the sham group (event rate ratio, 0.71; 95% CI, 0.64-0.99; P < 0.05). There were no study-related serious adverse events. ConclusionsSGB may provide effective treatment of VMS in women who seek nonhormonal treatments because of safety concerns and personal preference. The finding that SGB significantly reduces objectively measured VMS provides further evidence of efficacy. A larger trial is warranted to confirm these findings.

Confusion regarding anticoagulant coumarins in dietary supplements

rom the Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago/National Institutes of Health Center for Botanical Dietary Supplement Research in Women’s Health; Department of Obstetrics and Gynecology, University of Illinois at Chicago; and Department of Obstetrics and Gynecology, Northwestern University. his work was supported by grant P50 AT00155 provided jointly by the National Center for Complementary and Alternative Medicine (NCCAM), the Office of Dietary Supplements (ODS), the Office for Research on Women’s Health (ORWH), and the National Institute of General Medicine (NIGMS) of the National Institutes of Health (NIH). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NCCAM, National Cancer Institute, ODS, ORWH, NIGMS, or NIH. Nancy L. Booth received a National Research Service Award from NCCAM (F31 AT00804). eceived for publication July 30, 2004; accepted Aug 11, 2004. eprint requests: Richard B. van Breemen, PhD, Department of Medicinal Chemistry and Pharmacognosy, UIC/NIH Center for Botanical Dietary Supplement Research in Women’s Health, 833 S Wood St, M/C 781, University of Illinois at Chicago, Chicago, IL 60612. -mail: breemen@uic.edu lin Pharmacol Ther 2004;76:511-6. 009-9236/

Objective cognitive performance is related to subjective memory complaints in midlife women with moderate to severe vasomotor symptoms

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Discussion of a well-designed clinical trial which did not demonstrate effectiveness: UIC center for botanical dietary supplements research study of black cohosh and red clover

ObjectiveMemory complaints increase as women transition from the premenopausal stage to the postmenopausal stage. We explored the extent to which subjective memory complaints were associated with objective cognitive test performance, affective symptoms, and menopausal symptoms in midlife women with moderate to severe vasomotor symptoms. We predicted that subjective memory complaints would be related to affective symptoms and lower performance on tests of memory and attention. MethodsSixty-eight midlife women (mean age, 53 y; 54% African American) with at least 35 hot flashes per week completed the Memory Functioning Questionnaire, a battery of objective cognitive tests, a menopausal symptom inventory, and mood questionnaires. Linear regression analyses were conducted to examine predictors (symptoms and objective cognitive scores) of ratings on each of four Memory Functioning Questionnaire subscales and a validated single-item rating of current memory. ResultsNegative affect and delayed verbal memory predicted a single-item rating of current memory. Negative affect and poorer scores on tests of attention and working memory predicted Frequency of Forgetting. Lower positive affect, higher vasomotor symptoms, and increased age predicted lower Retrospective Memory Functioning. Increased age predicted Use of Mnemonics. ConclusionsThese findings strengthen the growing body of evidence indicating that women with memory complaints during the menopausal transition have an accurate appraisal of their memory function and that their complaints relate to affect and, to a lesser extent, vasomotor symptoms. Given that cognitive performance is within the reference range, these findings suggest that women can detect subtle changes in memory performance during the menopausal transition.

Stellate ganglion blockade and verbal memory in midlife women: Evidence from a randomized trial

The performance of a clinical trial for pharmaceutical agents is usually undertaken only after there is likely benefit demonstrated from the use of the putative agent. The consideration of botanical products as pharmaceutical agents must similarly go through a rigorous evaluation process. The present work reviews the recently published phase II study evaluating the effectiveness of black cohosh and red clover in a randomized trial with conjugated equine estradiol/medroxyprogesterone acetate and placebo for the treatment of menopausal symptoms. We analyze the possible reasons why this study failed to show benefit for either botanical product in reducing menopause-related vasomotor symptoms.