The effect of red clover isoflavones on menopausal symptoms, lipids and vaginal cytology in menopausal women: a randomized, double-blind, placebo-controlled study.

Background: The unexpected results of the Women's Health Initiative study have decreased the use of conventional hormone therapy (HT), changing physicians' and patients' attitudes towards HT and increasing their interest in alternative options. OBJECTIVE: The present study aimed to evaluate the effect of isoflavones contained in red clover extracts (Trifolium pratense) on menopausal symptoms, lipids and vaginal cytology in menopausal women. METHODS: Sixty postmenopausal women aged >40 years, non-users of HT, with Kupperman index score 15, were double-blindly randomized to receive either a commercially available red clover isoflavone supplement (80 mg/day) or placebo for 90 days. Subsequently, after a 7-day washout period, subjects switched to receive the opposite treatment for a further 90 days. Kupperman index score was determined and fasting blood and vaginal cytologic sampling performed at baseline, 90 and 180 days. RESULTS: Fifty-three women (88.3%) completed the trial. Mean age was 51.3 +/- 3.5 years, 69.7% of the women were aged 50 years or more. There was no significant effect on body mass index, weight or blood pressure after either treatment phase. Baseline Kupperman index score decreased significantly after each treatment phase, with the decrease more pronounced after the isoflavone phase (baseline: 27.2 +/- 7.7; after isoflavone: 5.9 +/- 3.9; after placebo: 20.9 +/- 5.3, p < 0.05). Red clover isoflavone supplementation significantly decreased the rate of menopausal symptoms and had a positive effect on vaginal cytology as expressed by improvement in karyopyknotic, cornification and basal cell maturation indices. Mean total cholesterol, low-density lipoprotein-cholesterol and triglyceride levels also decreased; however, only the latter was significantly lower compared with placebo. CONCLUSIONS: Compared with placebo, red clover isoflavone supplementation in postmenopausal women significantly decreased menopausal symptoms and had a positive effect on vaginal cytology and triglyceride levels.     

The effect of red clover isoflavone supplementation over vasomotor and menopausal symptoms in postmenopausal women

Objective. To evaluate the effect of red clover isoflavone supplementation over vasomotor and overall menopausal symptoms in postmenopausal women. Methods. One hundred and nine postmenopausal women aged 40 or more were assigned to randomly receive either two daily capsules of the active compound (80?mg red clover isoflavones, Group A) or placebo of equal appearance (Group B) for a 90-day period. After a washout period of 7 days, medication was crossed over and taken for 90 days more. Daily hot flush and night sweat frequency and overall menopausal symptom intensity (Kupperman Index) were measured at baseline, 90, 97 and 187 days. Results. Daily hot flush/night sweat frequency and Kupperman Index values were similar in both studied groups at baseline. All indices significantly decreased after red clover phase in Group A, corresponding, respectively to a 73.5%, 72.2% and 75.4% average decrement. These decrements were significantly higher than those observed for Group B after placebo phase (8.2%, 0.9% and 6.7% respectively). In Group A, after washout and placebo phases all values significantly increased. In Group B, all indices remained similar after placebo and washout phases, however significantly dropping after red clover treatment. These values were also significantly lower than those observed in Group A after placebo phase. No side effects were encountered after treatment with the active compound or placebo. Conclusion. Red clover isoflavone supplementation was more effective than placebo in reducing daily vasomotor frequency and overall menopausal intensity in postmenopausal women.     

Soy and red clover for mid-life and aging.

INTRODUCTION: Menopause is associated with mid-life, a time when many women begin to experience the signs and symptoms of aging, such as increases in blood pressure, changes in lipid profiles, loss of bone mass density, and diminished memory and cognition. Given the result of the Women's Health Initiative, many women no longer consider hormone therapy the first option for promoting healthy aging. Instead, they are turning to botanical and dietary supplement (BDS) products in place of hormone therapy. This paper reviews the evidence available for use of isoflavones from soy and red clover for the treatment or prevention of these health issues. METHODS: The MEDLINE and EMBASE databases were searched for articles relating to soy or red clover supplement use for prevention and/or treatment of heart disease, hyperlipidemia, osteoporosis, mood disorders and cognitive abilities. Studies were included if they were randomized, controlled trials and included peri- or postmenopausal women. RESULTS: Isoflavone products appear to be the most useful for improving lipid profiles; however, the evidence suggests that isoflavone extracts from soy are less effective than products containing soy protein or red clover isoflavones. Soy protein appears to reduce levels of total cholesterol and low density lipoprotein cholesterol, while red clover reduces levels of triglycerides and increases high density lipoprotein cholesterol. The data were somewhat less convincing, although promising, for increasing bone mass density and improving cognitive abilities. CONCLUSIONS: Research suggests that isoflavones found in soy foods and red clover appear to have a small but positive health effect on plasma lipid concentrations, bone mass density, and cognitive abilities. Given the lack of serious safety concerns in the short term, it would appear that including soy and red clover in the diet of postmenopausal women, not withstanding a soy allergy, might be beneficial.     

Phytoestrogens increase the capacity of serum to stimulate prostacyclin release in human endothelial cells

BACKGROUND: Both the estrogen receptor (ER) alpha and beta isoforms are expressed in the endothelium. The ER beta has been assigned a crucial role in normal vascular wall function. Prostacyclin has been ascribed a beneficial effect on vessel wall physiology. Isoflavones bind with higher affinity to ER beta. We investigated the hypothesis that their administration to postmenopausal women can promote endothelial prostacyclin production. METHODS: Twenty-five healthy postmenopausal women with mild climacteric symptoms received capsules containing 55 mg/day isoflavones derived from soy and red clover for 6 months. Cultured human umbilical vein endothelial cells (HUVECs) were exposed for 24 h to serum collected before the initiation of therapy and then after 3 and 6 months of continuous therapy. Prostaglandin production was measured in culture medium. RESULTS: In the presence of serum obtained after isoflavone treatment, the prostacyclin production increased significantly from 2.7 +/- 0.5 ng/mg protein at baseline to 3.4 +/- 0.7 ng/mg protein at 3 months (p < or = 0.05), and to 3.8 +/- 0.7 ng/mg protein at 6 months (p < or = 0.05 vs. baseline and 3 months' treatment). CONCLUSIONS: Serum obtained from postmenopausal women treated with isoflavones stimulates the capacity to produce prostacyclin by HUVECs in culture, an effect that could contribute to a beneficial cardiovascular effect of phytoestrogens.     

Effect of Trifolium pratense-derived isoflavones on the lipid profile of postmenopausal women with increased body mass index

Background. Since current clinical evidence indicates that conventional estrogen hormone therapy (HT) increases cardiovascular risk, alternatives to estrogens are growing in popularity, especially among high-risk populations.

Objective. To determine the effect of Trifolium pratense-derived isoflavone supplementation on the lipid profile of postmenopausal women with increased body mass index (BMI).

Methods. Sixty postmenopausal women aged > 40 years, HT non-users, were randomly assigned to one of two groups: either two capsules of T. pratense (80 mg red clover isoflavones) daily for a 90-day period or placebo of equal design. After a 7-day washout period, medication was crossed-over for another 90 days. Total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C) and lipoprotein A (LpA) levels were assessed at baseline, 90 and 180 days. Women were divided into two groups: those with increased BMI (≥25 kg/m²) and those with BMI < 25 kg/m².

Results. Fifty-three women (88.3%) completed the trial. T. pratense isoflavone supplementation had a positive effect on the lipid profile of women with increased BMI, evidenced by a significant decrease in TC, LDL-C and LpA levels.

Conclusions. Isoflavones derived from T. pratense are an attractive alternative therapeutic option for high-risk populations such as postmenopausal women with increased BMI and abnormal lipid profile.     

Phytoestrogens for treatment of menopausal symptoms: a systematic review

OBJECTIVE: To assess the efficacy and tolerability of phytoestrogens for treatment of menopausal symptoms. DATA SOURCES: We searched the Cochrane Library and MEDLINE from 1966 to March 2004, using a detailed list of terms related to phytoestrogens and menopausal symptoms and also hand-searched abstracts from relevant meetings. METHODS OF STUDY SELECTION: Randomized trials were eligible if they involved symptomatic perimenopausal or postmenopausal women, compared phytoestrogen with placebo or control, reported hot flush frequency or menopausal symptom scores, and were at least 4 weeks in duration. TABULATION, INTEGRATION, AND RESULTS: Data were extracted onto standardized forms using a prospectively developed protocol. Twenty-five trials involving 2,348 participants met criteria. At baseline, the mean age was 53.1 years, mean duration of menopause was 4.3 years, and mean daily hot flush frequency was 7.1. Mean study duration was 17 weeks. Trials were grouped into categories according to type of phytoestrogen: soy foods, beverages, or powders (n = 11); soy extracts (n = 9); and red clover extracts (n = 5). Of the 8 soy food trials reporting hot flush frequency outcomes, 7 were negative. Five trials of soy foods provided information to calculate effect sizes; these were in the small-to-medium range, favoring placebo in 3 trials and soy in 2. Of the 5 soy extract trials reporting hot flush frequency, 3 (including the 2 largest trials) were negative. Effect sizes were calculated for 2 soy extract trials: one favored placebo with small effect size and the other favored soy with moderate effect size. Red clover trials showed no improvement in hot flush frequency (weighted mean difference -0.60, 95% confidence interval -1.71 to 0.51). Adverse effects were primarily gastrointestinal and taste intolerance in the soy food and beverage trials. CONCLUSION: The available evidence suggests that phytoestrogens available as soy foods, soy extracts, and red clover extracts do not improve hot flushes or other menopausal symptoms.     

Soy isoflavone supplementation in postmenopausal women. Effects on plasma lipids, antioxidant enzyme activities and bone density

OBJECTIVE: To investigate isoflavone supplementation on plasma lipids, erythrocyte antioxidant enzyme activities and bone mineral density in postmenopausal women. STUDY DESIGN: Thirty-seven postmenopausal women were given 150 mg/d of isoflavone supplements twice daily for six months. Blood was sampled before and after supplementation, at three and six months. RESULTS: There were no significant differences in plasma total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride concentrations or erythrocyte antioxidant enzyme activities after three and six months of supplementation when compared with the baseline. No significant changes were noted in calcaneus bone mineral density after supplementing isoflavones for six months. CONCLUSION: The antioxidant effect of isoflavones in normal postmenopausal women is not obvious, and supplementation with isoflavone alone may not have a hypocholesterolemic effect. Since the duration of this study was too short with respect to bone density, longer studies are needed to clarify the bone-sparing effect of isoflavone supplementation.     

The short-term effects of different regimens of hormone replacement therapy on left ventricular structure and performance in healthy postmenopausal women. A prospective,controlled echocardiographic study

OBJECTIVE: To compare the short-term effects of different hormone replacement therapy (HRT) regimens on left ventricular structure and function in healthy postmenopausal women. METHODS: Forty-two apparently healthy postmenopausal women were evaluated prospectively in this controlled study. Subjects were divided into 4 groups. Ten subjects, who did not accept HRT or any other treatments, formed the control group. The remaining subjects were assigned to receive oral estradiol (2 mg/day) + norethisterone acetate (1 mg/day) (n = 11), transdermal estradiol (0.05 mg) + norethisterone acetate (0.25 mg) (n = 11) or tibolone (2.5 mg/day) (n = 10) therapy during 12 weeks. Echocardiography and Doppler techniques were used to assess the cardiac effects of different HRT regimens. RESULTS: After 12 weeks of treatment, there were significant increases in left ventricular ejection fraction (transdermal group: p = 0.008, oral group: p = 0.003, tibolone group: p = 0.005) and cardiac output (transdermal group: p = 0.003, oral group: p = 0.003, tibolone group: p = 0.021) in all treatment groups. In addition, in the transdermal group, a slight increase in left ventricular end-diastolic volume was significant (p = 0.046). CONCLUSION: These data suggest that oral and transdermal HRT regimens and tibolone may contribute to the improvement in left ventricular systolic function without having an effect on left ventricular structure after short-term administration in healthy postmenopausal women.     

The effect of postmenopausal hormone therapy with or without folic acid supplementation on serum homocysteine level.

OBJECTIVE: To evaluate the effects of postmenopausal hormone therapy (HT) with or without the addition of folic acid (FA) on serum homocysteine levels in a randomized, placebo-controlled design. Additionally, a non-randomized control group with no treatment was included. METHODS: Forty non-hysterectomized healthy postmenopausal women were randomly allocated to receive either oral continuous combined HT (0.625 mg conjugated equine estrogen with 2.5 mg medroxyprogesterone acetate daily) and oral folic acid (5 mg/day, n = 20) or HT and placebo (n = 20) for 3 months. A control group (n = 15) did not receive any study medication and was followed in the same manner. The fasting total serum homocysteine level was measured by fluorescence polarization immunoassay with a sensitivity of < 0.5 micromol/l. Serum levels of folate, estrogen and lipid profile were also followed. RESULTS: The mean age of the postmenopausal women was 52 +/- 6 years. Baseline homocysteine level was the highest in the HT + FA group (9.96 +/- 2.82 micromol/l), compared to HT + placebo (9.64 +/- 1.89 micromol/l) and control groups (9.01 +/- 1.83 micromol/l) (ANCOVA, p = 0.022). Low baseline folate and vitamin B12 levels contributed significantly to the high level of baseline homocysteine in the HT + FA group. The addition of FA to HT led to a significant decrease in the serum homocysteine level from the baseline level of 9.96 +/- 2.82 micromol/l to the final level of 8.92 +/- 2.53 micromol/l (p = 0.023). On the other hand, HT alone (HT + placebo group) significantly increased the serum homocysteine level from 9.64 +/- 1.89 micromol/l to 10.22 +/- 1.77 micromol/l without a decline in serum folate level (p = 0.045). The serum homocysteine level in the control group did not change significantly (from 9.01 +/- 1.83 micromol/l to 9.58 +/- 2.05 micromol/l, p = 0.29). CONCLUSIONS: Three months of oral continuous combined HT increased the fasting total serum homocysteine level without affecting the serum folate level. Lowering the homocysteine level in postmenopausal woman on HT is achievable by folic acid supplementation.     

Influence of a continuous combined HRT (2 mg estradiol valerate and 2 mg dienogest) on postmenopausal depression.

OBJECTIVE: This randomized, double-blind, placebo-controlled study was planned to investigate the effects of continuous combined hormone replacement therapy (HRT) with 2 mg estradiol valerate and 2 mg dienogest (Climodien/Lafamme) over 24 weeks on postmenopausal depression. METHOD: A total of 129 patients with a mild to moderate depressive episode according to ICD-10: F32.0, F32.1 in the context of a postmenopausal syndrome (ICD-10: N95.1) and a baseline score in the Hamilton depression scale (HAMD) > or =16 were included in the study. The primary target variable was depression severity as measured by the HAMD after 24 weeks of treatment. A four-point difference between HRT and placebo at the end of the study and, in addition, a final score < or =8 (corresponding to an improvement of > or =50% as compared to baseline) for the individual patient (responders analysis) were considered clinically relevant. Clinical global impression (CGI) of investigators (therapeutic and side-effects) at the end of the study was investigated. Secondary effects of HRT on depression severity caused by its effect on vasomotor symptoms or sleep disturbances (domino hypothesis) were taken into consideration. Also, the study addressed the question of whether the effect of HRT on depression severity depends on a history of premenstrual syndrome (PMS) or postnatal depression (PND). RESULTS: The results showed a clear and clinically relevant reduction of depression severity under HRT after 24 weeks of treatment and superiority over placebo (p < 0.0005) in spite of a strong placebo effect. The effects of the estrogen-progestin combination thereby seemed only partially to be dependent on the improvement of vasomotor symptoms and sleep disturbances. Also, the effects of HRT could not be shown to be dependent on a history of PMS and/or PND, even though women with and without this history clearly differed in baseline depression scores (p < 0.0001). The assessment of CGI was positive: whereas HRT was clearly superior to placebo with regard to therapeutic effects (p = 0.0014), there were no differences with regard to side-effects (p = 0.35). CONCLUSION: The combination of 2 mg estradiol valerate and 2 mg dienogest can be regarded as an effective and safe treatment option for women with mild to moderate depression in the context of postmenopausal syndrome.     

Effect of raloxifene on sexual function in older postmenopausal women with osteoporosis

OBJECTIVE: To assess the effect of raloxifene compared with placebo on sexual function in older postmenopausal women undergoing therapy for the treatment of osteoporosis. METHODS: A subset (12%) of English-speaking women in the United States and Canada participating in the Multiple Outcomes of Raloxifene Evaluation Trial were asked to complete a sexual function questionnaire at baseline and after 36 months of treatment. The Multiple Outcomes of Raloxifene Evaluation Trial is a multicenter, randomized, blinded, placebo-controlled clinical trial, in which 7,705 postmenopausal women with osteoporosis were randomly assigned to one of three groups: raloxifene hydrochloride 60 mg per day or 120 mg per day or placebo. In this substudy, 943 women completed the sexual function questionnaire at both visits. Because preliminary analyses showed no differences by raloxifene dose (n = 302 for 60 mg per day; n = 322 for 120 mg/day), the two groups were combined and compared with the placebo group (n = 319). For the given sample size, we had 80% power (alpha =.05, two-sided, ratio of raloxifene to placebo = 2:1) to detect a 10%-16% difference in the proportion of women experiencing no change in sexual function between placebo and treatment groups. RESULTS: Overall, sexual function and changes in sexual function from baseline to study end between the raloxifene and placebo groups did not differ. In particular, there were no differences in sexual desire or frequency of sexual activity between the groups. Among sexually active women, there were no differences in enjoyment, satisfaction, orgasm, or reported sexual problems. CONCLUSION: Sexual function in older postmenopausal women with osteoporosis is not affected by treatment with raloxifene.     

Lack of effect of isoflavonic phytoestrogen intake on leptin concentrations in premenopausal and postmenopausal women

Objective: To assess the effect of soy isoflavone ingestion on plasma leptin concentrations in premenopausal and postmenopausal women.

Design: Randomized, crossover studies, with blinding of participants and laboratory personnel.

Setting: Procedures involving free-living individuals were carried out at the University of Minnesota General Clinical Research Center.

Patient(s): Fourteen regularly cycling premenopausal women, and 18 postmenopausal women.

Intervention(s): Each premenopausal participant consumed, on a daily basis, each of three soy protein powders containing different levels of isoflavones for three menstrual cycles plus 9 days, with plasma samples collected every other day the last 6 weeks of each diet period. Similarly, each postmenopausal participant consumed each of the three powders for 93 days, with plasma samples collected daily on days 64 to 66 and 92 to 94 of each diet period. The powders, dosed on a per-kilogram body weight basis, provided mean isoflavone intakes of 8, 65, and 130 mg/day, for the control, low-isoflavone, and high-isoflavone diet periods, respectively.

Main Outcome Measure(s): Plasma leptin concentrations.

Result(s): Isoflavone intake had essentially no effect on leptin concentrations in either premenopausal or postmenopausal participants. Concentrations in the premenopausal women were higher during the periovulatory and midluteal phases as compared to the early follicular and midfollicular phases.

Conclusion(s): Despite the well-documented effect of estrogens to enhance leptin production, even high levels of isoflavone consumption do not alter leptin concentrations in women. Further studies are needed to more precisely delineate the nature of estrogenic and/or antiestrogenic effects of isoflavones in humans.     

Effect of pure genistein on bone markers and hot flushes.

OBJECTIVE: To evaluate the effect of 90 mg of daily genistein on markers of bone turnover and menopausal symptoms. DESIGN: This was a cross-over, placebo-controlled study involving 100 postmenopausal women. Subjects were randomly assigned to daily genistein or placebo for 6 weeks and crossed over to the alternative preparation for the following 6 weeks. Pure genistein was processed and encapsulated in accordance with British Pharmacopoeia standards. Each capsule contained 90 mg of pure genistein while the placebo contained just the recipients. RESULTS: In women with significant hot flushes (score (intensity x number) > or = 9), genistein reduced symptoms by 30% compared to baseline and the difference compared to placebo was statistically significant. No effect was observed on biochemical markers of bone turnover, possibly due to the short duration of each arm of the study. Genistein reduced osteocalcin, a marker of bone formation, by 3.6% compared to baseline and 0.31% compared to placebo (p = 0.81 and 0.40, respectively). Genistein increased cross-link telopeptide, a marker of bone resorption, by 1.8% compared to baseline and 0.29% compared to placebo; both differences were not statistically significant (p = 0.078 and 0.88, respectively). CONCLUSION: Pure genistein at a dose of 90 mg per day appears to reduce the number of hot flushes in postmenopausal women but the effect is mild.     

The effect of tibolone in postmenopausal women receiving tamoxifen after surgery for breast cancer: a randomised, double-blind, placebo-controlled trial

OBJECTIVE: To assess the effects of tibolone on climacteric symptoms, endometrium and serum lipid/lipoproteins in postmenopausal women receiving tamoxifen after surgery for breast cancer. DESIGN: Double-blind, randomised, placebo-controlled, multicentre pilot study. SETTING: Hospital outpatient clinic. SAMPLE: Seventy postmenopausal women receiving tamoxifen following surgery for early breast cancer. METHODS: Women received 20 mg/day oral tamoxifen plus either 2.5 mg/day oral tibolone or placebo for 12 months. MAIN OUTCOME MEASURES: Frequency and severity of hot flushes (diary cards); intensity of hot flushes and sweats (Landgren scale); interference of hot flushes and sweats with normal life; frequency and intensity of other climacteric symptoms; endometrial thickness and histology; vaginal bleeding; breast cancer recurrence and serum lipid/lipoproteins. RESULTS: Daily card data showed no change in the daily number of hot flushes with either tibolone or placebo (P= 0.219) after three months. There was a significant reduction in the severity of flushes with tibolone compared with placebo (-0.4 vs 0.2, P= 0.031). The Landgren scale showed a mean change in the number of hot flushes of -0.6 with tibolone and +1.1 with placebo after 12 months (P= 0.022). Endometrial biopsies were normal and vaginal bleeding was similar in both groups. A significant decrease in triglycerides (-23% vs 1.4%) and HDL (-12% vs 19%) was seen with tibolone compared with placebo after 12 months. CONCLUSIONS: Tibolone prevented an increase in hot flushes in postmenopausal women given tamoxifen following surgery for breast cancer without untoward effects on the endometrium. Beneficial effects on serum lipid profile were noted.     

Effects of ospemifene, a novel SERM, on biochemical markers of bone turnover in healthy postmenopausal women.

Ospemifene is a novel selective estrogen receptor modulator (SERM). Here we studied the effects of ospemifene on bone turnover in postmenopausal women. This was a randomized, double-blind study in which 159 healthy postmenopausal women received 30 (n = 40), 60 (n = 40) or 90 mg (n = 40) of ospemifene or placebo (n = 39) for 3 months. Bone resorption was assessed by measuring the urinary outputs of N- and C-terminal crosslinking telopeptides of type I collagen (NTX and CTX, respectively). Bone formation was assessed by measuring the levels of procollagen type I N propeptide (PINP), procollagen type I C propeptide (PICP), and bone-specific alkaline phosphatase (bone ALP) in serum. All markers were studied at baseline, 3 months, and 2-4 weeks after cessation of the medication. Ospemifene decreased bone resorption dose-dependently, as seen from falls in NTX by 6.1, 9.4 and 12.9% in the 30, 60 and 90 mg ospemifene groups, respectively (p < 0.05 for all dose levels when compared to placebo). CTX values decreased in the 90 mg ospemifene group by 4.8% (p < 0.05). A dose-dependent decrease was also observed in the bone formation markers: PINP values decreased by 9.8 (p < 0.05) and 15.3% (p < 0.01), and PICP values by 12.0 and 11.9% in the 60 and 90 mg ospemifene groups, respectively. Bone ALP decreased in 60 and 90 mg ospemifene groups by 1.9 and 2.6%, respectively (p < 0.05 for both dose levels when compared to placebo). These results show that ospemifene is effective in reducing bone turnover in postmenopausal women.     

Neither long-term treatment with raloxifene nor hormone replacement therapy modulate cardiac function in healthy postmenopausal women: two randomized, placebo-controlled, 2-year studies

OBJECTIVE: Our purpose was to investigate the long-term effects of raloxifene, compared with opposed and unopposed estrogen replacement therapy, on echocardiographic parameters of left ventricular systolic function in healthy postmenopausal women. A total of 157 women were studied in 2 randomized, double-blind, placebo-controlled, 2-year studies. STUDY DESIGN: In study I, 60 postmenopausal women who had undergone hysterectomy received daily raloxifene, 60 mg (n = 15); raloxifene, 150 mg (n = 15); conjugated equine estrogens (CEE), 0.625 mg (n = 15); or placebo (n = 15). In study II, 97 postmenopausal women who had not undergone hysterectomy received daily raloxifene, 60 mg (n = 24); raloxifene, 150 mg (n = 24); CEE, 0.625 mg, plus medroxyprogesterone acetate (MPA), 2.5 mg (n = 24); or placebo (n = 25). M-mode, quantitative 2-dimensional and Doppler echocardiographic measurements were performed at baseline and after 1 and 2 years. RESULTS: Neither after 1 year nor after 2 years of treatment were echocardiographic parameters found to differ from baseline in both raloxifene groups, as well as in the unopposed CEE and the CEE/MPA groups, compared with the placebo group. CONCLUSION: Within 2 years of raloxifene treatment, no effect on echocardiographic parameters of left ventricular systolic function was found. Unopposed CEE or CEE/MPA also showed no effect.     

Benefits of soy isoflavone therapeutic regimen on menopausal symptoms

OBJECTIVE:To examine the change in menopausal symptoms and cardiovascular risk factors in response to 4 months of daily 100-mg soy isoflavone in postmenopausal women. METHODS: In this double-blind, placebo-controlled study, 80 women were randomly assigned to isoflavone (n = 40) and placebo (n = 40) treatment. The menopausal Kupperman index was used to assess change in menopausal symptoms at baseline and after 4 months of treatment. Cardiovascular risk factors were assessed by evaluating plasma lipid levels, body mass index, blood pressure, and glucose levels in the participants. To examine the effects of this regime on endogenous hormone levels, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and 17 beta-estradiol were measured. Transvaginal sonography was performed to quantify endometrial thickness. RESULTS: The data showed a decrease in menopausal symptoms (P <.01, paired t test, two-tailed, between baseline and isoflavone groups, and P <.01, unpaired t test, between placebo and isoflavone groups). Total cholesterol and low-density lipoprotein decreased significantly in the isoflavone group compared with the baseline or placebo group (P <.001, paired t test, two-tailed, between baseline and isoflavone groups, and P <.01, unpaired t test, between placebo and isoflavone groups). The isoflavone treatment appeared to have no effect on blood pressure, plasma glucose, and high-density lipoprotein and triglyceride levels. CONCLUSION: This study suggests that isoflavone 100-mg regime treatment may be a safe and effective alternative therapy for menopausal symptoms and may offer a benefit to the cardiovascular system.     

Hormone replacement therapy and plasma homocysteine levels.

OBJECTIVE: To compare the effects of 4 and 12 weeks of combined estradiol-progestogen replacement with unopposed estradiol therapy on fasting plasma total homocysteine concentrations in healthy postmenopausal women. METHODS: In this prospective, 12-week study in healthy postmenopausal women, we randomly assigned 59 women to sequentially combined daily 2 mg estradiol (E2) plus either trimegestone 0.5 mg daily or dydrogesterone 10 mg daily (n = 28), or to unopposed daily 2 mg estradiol (n = 16), or to placebo (n = 15). RESULTS: Fasting plasma total homocysteine concentrations decreased by 9.4% in the combined estradiol-progestogen group and by 5.1% in the estradiol-only group, and they increased by 2.4% in the placebo group (analysis of covariance: combined hormone replacement therapy compared with placebo (P = .02); combined therapy compared with estradiol (P = .23); and estradiol compared with placebo (P = .26). Reductions were detectable after 4 weeks of combined estradiol-progestogen treatment. The data suggest an additional progestogen-related reduction in homocysteine levels of 0.7 micromol/L and 0.4 micromol/L after 4 and 12 weeks, respectively. Women with a baseline homocysteine concentration in the highest quartile had significantly greater reductions in homocysteine compared with women with an initial homocysteine value in the lowest quartile. CONCLUSION: Fasting total homocysteine concentrations were significantly reduced by combined estradiol-progestogen replacement. Women with high homocysteine levels at baseline benefit the most. The progestogens used in this study did not have an unfavorable effect on homocysteine metabolism.     

Individual differences in equol production capability modulate blood pressure in tibolone-treated postmenopausal women: lack of effect of soy supplementation.

OBJECTIVES: Equol, a gut bacterial metabolite of the isoflavone daidzein, has been associated with beneficial health effects. Recent studies indicate that women with intestinal capacity to convert daidzein to equol also have the capacity to alter steroid metabolism and bioavailability of estrogens. METHODS: We evaluated whether individual equol production capability, while not consuming soy supplement, was associated with lower blood pressure in postmenopausal women using tibolone. In addition, in a randomized, placebo-controlled, cross-over trial we assessed the effect of soy supplementation on blood pressure in both equol-producing (n = 20) and non-equol-producing (n = 20) women using tibolone. Blood pressure was recorded with a validated oscillometric technique. RESULTS: The circulating equol levels rose 20-fold in the equol producers and 1.9-fold in the non-equol producers. At baseline, systolic blood pressure (129.9 +/- 2.6 vs. 138.5 +/- 3.1 mmHg, p = 0.02), diastolic blood pressure (72.2 +/- 1.5 vs. 76.6 +/- 1.3 mmHg, p = 0.01) and mean arterial blood pressure (93.5 +/- 1.7 vs. 99.9 +/- 1.8 mmHg, p = 0.007) were lower in equol producers compared to non-equol producers. Soy supplementation had no effect on blood pressure in either group, whereas the baseline differences persisted. CONCLUSIONS: Postmenopausal women using tibolone characterized as equol producers had lower blood pressure compared to non-equol producers. Soy supplementation for 2 months had no blood pressure-lowering effect.     

Association of tibolone and fluoride displays a pronounced effect on bone mineral density in postmenopausal osteoporotic women.

A double-blind, placebo-controlled, randomized, prospective two-center study was carried out to assess the effects of tibolone + fluoride versus placebo + fluoride therapy on trabecular and cortical bone in postmenopausal osteoporotic women. Ninety-four subjects (mean age 61.1 years, postmenopausal 13.5 years on average) with low bone mineral density (BMD) at baseline were randomized to 2.5 mg of tibolone (Org OD 14, Livial) plus 26.4 mg of fluoride (Fluocalcic) or placebo plus 26.4 mg of fluoride daily over 2 years; 55 (58.5%) subjects completed the study, the main reason for discontinuation being untoward gastrointestinal effects. BMD at the lumbar spine was measured by both dual photon absorptiometry (DPA) and dual-energy X-ray absorptiometry (DXA), and at the hip by DXA at 6-month intervals. Baseline values (DXA, g/cm2) for tibolone + fluoride and placebo + fluoride groups were 0.733 and 0.744 for the lumbar spine, and 0.761 and 0.788 for the hip. Change from baseline and percentage change from baseline were calculated for the intent-to-treat and completers groups. An analysis of variance (ANOVA) model or Wilcoxon test was used for statistical evaluation. There was a mean increase in BMD at the lumbar spine measured by DPA of 25.3% and 12.3% in tibolone + fluoride and placebo + fluoride groups, respectively (p = 0.01); with DXA, respective changes were 32.6% and 14.0% (p = 0.013). Data on BMD at the hip showed mean increases of 7.9% and 2.6% for the tibolone + fluoride and placebo + fluoride groups, respectively. We conclude that combined tibolone + fluoride treatment induces a highly significant increase in BMD at the lumbar spine without simultaneous loss of the cortical bone allowing for a meaningful reduction of the fluoride dose when given in combination with tibolone.