Climacteric Complaints Research Articles

Tibolone: Clinical recommendations and practical guidelines: A report of the International Tibolone Consensus Group

An international multidisciplinary panel of experts in the management of the menopause met at the 4th Amsterdam Menopause Symposium in October 2004 to determine the specific place of tibolone, a synthetic steroid with a unique clinical profile, within the wide range of currently available postmenopausal therapy options. The consensus was that tibolone is a valuable treatment option for women with climacteric complaints. As well as relieving vasomotor symptoms, tibolone has positive effects on sexual well-being and mood, and improves vaginal atrophy and urogenital symptoms. Prevention of bone loss with tibolone is comparable to that seen with estrogen therapy (ET) and estrogen/progestogen therapy (EPT). As tibolone rarely causes endometrial proliferation, no additional progestogen is required. It also has good tolerability, being associated with a low incidence of vaginal bleeding and of breast pain. Tibolone does not increase mammographic density. Absolute numbers of women at increased risk for breast cancer are estimated to be low or absent with both tibolone and ET, and the risk with tibolone should be significantly lower than that with EPT. Tibolone might therefore be preferable to EPT in certain women who have not been hysterectomised. Based on the evidence available, the panel proposed a number of subgroups of postmenopausal women with vasomotor symptoms in whom tibolone might have added value; these included women with sexual dysfunction, mood disorders, fibroids and urogenital complaints, as well as those with breast tenderness or high mammographic breast density with EPT use.

Blutungsmuster, Wirksamkeit und Akzeptanz einer niedrig dosierten HRT mit Estradiol/Norethisteronacetat bei direkter Umstellung von oraler Kontrazeption

Fragestellung: Frequenz und Stärke der unter jeder kombinierten Estrogen/Gestagentherapie (HRT) möglichen initialen Blutungen sind unter anderem abhängig von hormonalen Vorbehandlungen und somit möglicherweise auch von einer vorausgegangenen oralen Kontrazeption. Bislang liegt keine Studie vor, in der nach direkter Umstellung von Kontrazeptiva Blutungsmuster, Wirksamkeit und Akzeptanz unter HRT gezielt untersucht wurden.

Postmenopausal hormone therapy and breast cancer: What is the problem?

Observational studies provide evidence that breast cancer risk is increased with long-term oral use of postmenopausal estrogen replacement therapy (ET). Various large cohort studies have shown that the addition of a progestogen in combined hormone replacement therapy (EPT) increases this risk further. Prospective, randomized controlled trials have confirmed this for the continuous combined regimen. So, why not tell our patients, “Stop using ET and EPT, it is dangerous to your health!”? The answer is: there are too many problems to allow such an oversimplified, definite statement. What is the problem? There is more than one! The problems are as follows: • There are many observational studies, but these are not consistent in their results. • Relative risk increases, if any, are small and thus often statistically non-significant. • Observational studies have inherent biases that cannot be corrected for; therefore evidence should come from randomized clinical trials (RCTs). • There are no RCTs that provide evidence as to the breast cancer risk with ET, compared to EPT in the same study population. • In the three large RCTs available, the populations studied are: not representative, too old and without climacteric complaints, and therefore lacking any indication for postmenopausal hormone therapy (HT). • The data obtained thus far do not apply to non-oral routes, neglect the difference in progestogens, and do not address tibolone, a valuable alternative to classical HT in Europe. • And finally, are these epidemiological findings biologically plausible? Can estrogens cause breast cancer and why then does the Women's Health Initiative (WHI) RCT not find this? And how can the addition of a progestogen increase the ET risk further as progestogens are pro-apoptotic and down-regulate estrogen receptors as well as local estrogen biosynthesis? In conclusion, we have a problem as we cannot formulate any general advice that holds for the majority of European postmenopausal women due to lack of consistency, lack of biological plausibility, and lack of relevance of randomized clinical trial data to our daily practical work. So, we have a problem and not a firm basis for undisputable statements.

Associated factors with urogenital score in natural and surgical menopause

Objective: To anticipate the factors associated with urogenital symptoms in both natural and surgical menopause. Methods: A retrospective analysis was performed comprising 267 cases with spontaneous menopause and 87 surgical menopause cases without any use of hormone replacement therapy. Sociodemographic characteristics, reproductive and medical history, urogenital scale and psychological subscale of Greene Climacteric Scale were assessed and correlated with the age of menopause, time past since last menstrual period, parity, body mass index (BMI), mode of delivery among two groups. Results: Mean age of women enrolled to the study were 46.8 ± 0.3 years and 44.4 ± 0.25 years, for natural and surgical menopause cases, respectively. Mean parity had no correlation with urogenital scale in two groups. However, a positive correlation was apparent between the time since last menstrual period, psychological subscore of Green Climacteric Scale and urogenital score in both women with natural and surgical menopause. BMI was negatively correlated with urogenital score among two groups ( r p = −0.85, p = 0.04). Conclusions: Intensity and frequency of urogenital symptoms and climacteric complaints as expressed in the Greene Climacteric Scale increase during menopausal transition. Care should be taken to ameliorate the quality of life (QOL) and to confront these problems in post-menopausal women.

Efficacy of Cimicifuga racemosa on climacteric complaints: A randomized study versus low-dose transdermal estradiol

Objective To investigate, in a randomized clinical study, the efficacy of an isopropanolic aqueous extract of Cimicifuga racemosa (CR) on climacteric complaints in comparison with low-dose transdermal estradiol (TTSE2). Hormonal parameters, lipid profile and endometrial thickness were also evaluated.Methods Sixty-four postmenopausal women were enrolled and over the course of 3 months filled in a diary recording the number of hot flushes per day. Other climacteric symptoms (vasomotor and urogenital symptoms) as well as anxiety and depression, were evaluated at baseline and after 3 months. Gonadotropins (follicle-stimulating hormone (FSH), luetinizing hormone (LH)), prolactin (PRL), 17β-estradiol (17β-E2) and cortisol, lipid profile (total cholesterol high-density lipoprotein (HDL)/low-density lipoprotein (LDL)-cholesterol, triglycerides, liver function (glutamic–oxalacetic transaminase, glutamic–pyruvic transaminase) and endometrial thickness were measured. Patients were randomly allocated to receive, for 3 months, either 40 mg isopropanolic aqueous CR extract daily or 25 μg TTSE2 every 7 days plus dihydrogesterone 10 mg/day for the last 12 days of the 3-month estradiol treatment.Results Both CR and low-dose TTSE2 significantly reduced the number of hot flushes per day (p < 0.001) and vasomotor symptoms (p < 0.001), starting at the first month of treatment. Such a positive effect was maintained throughout the 3 months of observation, without any significant difference between the two treatments. An identical effect was evident also for both anxiety (p < 0.001) and depression (p < 0.001) which were significantly reduced following 3 months of both CR and low-dose TTSE2. Total cholesterol was unchanged by CR treatment but significantly (p < 0.033) reduced by 3 months of low-dose TTSE2. A slight but significant increase of HDL-cholesterol (p < 0.04) was found only in women treated with CR, while LDL-cholesterol levels were significantly lowered by 3 months of both CR (p < 0.003) and low dose TTSE2 (p < 0.002). Triglycerides were not affected by both treatments, nor was liver function. FSH, LH and cortisol were not significantly affected after the 3-month treatment, while PRL (p < 0.005) and 17-βE2 (p < 0.001) were increased slightly only by low-dose TTSE2. Endometrial thickness was not affected by either CR or low-dose TTSE2.Conclusions CR (40 mg/day) may be a valid alternative to low-dose TTSE2 in the management of climacteric complaints in those women who cannot be treated with or just refuse conventional strategies.

Comparing the Effects of Estrogen and an Herbal Medicine on Peripheral Blood Flow in Post-menopausal Women with Hot Flashes: Hormone Replacement Therapy and Gui-Zhi-Fu-Ling-Wan, a Kampo Medicine

We investigated the association between blood flow in the extremities and hot flashes, and compared change in blood flow following hormone replacement therapy (HRT) and Gui-zhi-fu-ling-wan (Keishi-bukuryo-gan), a herbal therapy in post-menopausal women with hot flashes. Three hundred and fifty-two post-menopausal women aged 46-58 years (mean: 53.4 +/- 3.6 years) with climacteric complaints participated in the study. One hundred and thirty-one patients with hot flashes were treated with HRT (64 cases) or herbal therapy (67 cases). Blood flow was measured with laser doppler fluxmetry under the jaw, in the middle finger and in the third toe. Post-menopausal women with hot flashes (129 cases) showed significantly higher blood flow under the jaw (13.6 +/- 4.13) than women without hot flashes (166 cases) (5.48 +/- 0.84) (p < 0.0001). Blood flow at this site decreased significantly with either therapy (p < 0.0001). On the other hand, the administration of Gui-zhi-fu-lingwan significantly increased (p = 0.002) the blood flow in the lower extremities, whereas HRT decreased the blood flow. Thus, we have demonstrated that Gui-zhi-fu-ling-wan did not affect the activity of vasodilator neuropeptides on sensory neurons of systemic peripheral vessels uniformly. Therefore, Gui-zhi-fu-ling-wan, rather than HRT, is suggested as an appropriate therapy for treatment of hot flashes in the face and upper body with concomitant coldness in the lower body, which is one of the symptoms of menopause.

Cimicifuga racemosa dried ethanolic extract in menopausal disorders: a double-blind placebo-controlled clinical trial

Objectives: To compare the efficacy and safety of the black cohosh root extract Cr 99 with placebo in women with climacteric complaints. Methods: A multicenter, randomized, placebo-controlled, double-blind, parallel group study was conducted in 122 menopausal women (intention-to-treat population) with ≥3 hot flashes a day, treated over 12 weeks. Two main efficacy measures – weekly weighted score of hot flashes and Kupperman Index – and secondary efficacy variables, e.g. Menopause Rating Scale, were defined. Routine safety laboratory parameters and adverse events were documented. Results: The primary efficacy analysis showed no superiority of the tested black cohosh extract compared to placebo. However, in the subgroup of patients with a Kupperman Index ≥ 20 a significant superiority regarding this index could be demonstrated ( P < 0.018). A decrease of 47% and 21% was observed in the black cohosh and placebo group, respectively. The weekly weighted scores of hot flashes ( P < 0.052) and the Menopause Rating Scale ( P < 0.009) showed similar results. Prevalence and intensity of the adverse events did not differ in the two treatment groups. Conclusions: The results indicate a superiority of the tested Cimicifuga racemosa extract compared to placebo in patients with menopausal disorders of at least moderate intensity according to a Kupperman Index ≥ 20, but not in the intention-to-treat population as a whole.

The impact of a monophasic continuous estro-progestogenic treatment on Latin American menopausal women

Objective: The present study was undertaken to assess the impact, effectiveness and safety of a monophasic hormone replacement treatment (HRT) for continuous use with regards to the clinical effects, bleeding patterns and lipid profile of menopausal women in four Latin American countries. Design: Three hundred and six postmenopausal women with natural menopause and uterus present were recruited. This was a multicentre prospective, clinical trial; the participating countries were Brazil (BR), Colombia (CO), Mexico (MX) and Argentina (AR). The study period was 12 months. The HRT regime was formulated in tablets containing 2 mg estradiol E 2 and 1 mg norethisterone acetate (NETA); one visit every 3 months was solicited. Methods: HRT was given as one tablet every day without interruption for 1 year. Climacteric complaints, side-effects, reason for discontinuation, bleeding patterns, lipid profile at baseline and 12 months of treatment were documented. Results: There were no significant differences between the four populations on clinical measurements. Thirty-four women discontinued, 13 for bleeding problems. The five most common side-effects were mastalgia, bleeding problems, headache, pelvic pain and nausea. 44.8% of women experienced scanty vaginal bleeding during the first 3 months of therapy. Ninety seven percent of women had amenorrhea at the end of the study in MX, BR and AR, and 100% in CO. Body weight was constant during the study, and no correlation was found between body weight and total days with bleeding. The Kupperman index score was used to evaluate the climacteric complaints, and the score decreased from a mean of 25.4 to 5.1 at 12-months visit. Total cholesterol levels were significantly reduced in BR and CO ( P < 0.05) between baseline and the final sample; serum triglycerides remained unchanged, HDL-cholesterol was significantly increased in MX ( P < 0.05), and LDL-cholesterol was significantly reduced in CO ( P < 0.05). The results of this 1-year study emphasize that a continuous combined HRT regimen with 2 mg E2/1 mg NETA is an attractive alternative for postmenopausal women who are at least 1 year after their menopause and optimally 2 years after their menopause. Although the combination of 2 mg E2 with 1 mg NETA in a continuous combined therapy scheme has been in use in the Nordic countries for over a decade and in Latin America for the last 6 years, there have been no previous published reports on its effectivity in Latin American women. This publication reports the experience in a group of 306 Latin American women, and it is the first Latin American publication with this formulation.

Relationship between climacteric symptoms and serum galanin levels in post-menopausal women

The aim of the study was to evaluate the possible relationship between climacteric symptoms and serum galanin concentrations in post-menopausal women. We studied 38 women who attended the Department of Gynecological Endocrinology in Poznan because of climacteric complaints. The control group comprised 16 women [mean age 22.2 yr (SD+/-0.9 yr), range 18-24 yr] who were menstruating regularly and had normal body mass index. We evaluated the severity of climacteric symptoms using the Kupperman scale and we measured 17beta-estradiol, FSH and galanin serum concentrations by radioimmunoassay. The mean serum galanin concentration was 18.7 pg/ml (SD+/-16.1 pg/ml) in the study group and 21.9 pg/ml (SD+/-9.4 pg/ml) in the control group. The difference was not statistically relevant. The mean serum galanin concentration was 15.9 pg/ml (SD+/-12.6 pg/ml) in the group of patients with mild and moderate climacteric symptoms and 29.5 pg/ml (SD+/-23.3 pg/ml) in the group of patients with severe climacteric symptoms. The difference between the two groups was statistically significant (Student t-test: p<0.05). Climacteric patients with nervousness had lower serum galanin concentration than patients without this symptom (Student t-test: p<0.05). a) Serum galanin concentration in post-menopausal women is related to severity of climacteric syndrome; b) the presence of nervousness in post-menopausal women is related to lower serum galanin level.

Tibolone is metabolized by the 3alpha/3beta-hydroxysteroid dehydrogenase activities of the four human isozymes of the aldo-keto reductase 1C subfamily: inversion of stereospecificity with a delta5(10)-3-ketosteroid.

Tibolone is used to treat climacteric complaints and prevent osteoporosis. These beneficial effects are exerted via its 3alpha-and 3beta-hydroxymetabolites. Undesirable stimulation of the breast and endometrium is not apparent. Endometrial stimulation is prevented by the progestogenic activity of its Delta4-ene metabolite. The enzymes responsible for the formation of these active metabolites are unknown. Human aldo-keto reductase (AKR)1C isoforms have been shown to act as 3alpha/3beta-hydroxysteroid dehydrogenases (HSDs) on 5alpha-dihydrotestosterone (5alpha-DHT). We show that AKR1Cs also efficiently catalyze the reduction of the Delta(5(10))-3-ketosteroid tibolone to yield 3alpha- and 3beta-hydroxytibolone. Homogeneous recombinant AKR1C1, AKR1C3, and AKR1C4 gave similar catalytic profiles to those observed with 5alpha-DHT. AKR1C1 catalyzed exclusively the formation of 3beta-hydroxytibolone, AKR1C3 showed weak 3beta/3alpha-HSD activity, and AKR1C4 acted predominantly as a 3alpha-HSD. Whereas AKR1C2 acted as a 3alpha-HSD toward 5alpha-DHT, it functioned exclusively as a 3beta-HSD on tibolone. Furthermore, strong substrate inhibition was observed for the AKR1C2 catalyzed reduction of tibolone. Using NAD+, the 3-hydroxymetabolites were efficiently oxidized by homogeneous recombinant AKR1C2 and AKR1C4. However, because of potent inhibition of this activity by NADPH, AKR1Cs will probably act only as 3-ketosteroid reductases in vivo. Molecular docking simulations using crystal structures of AKR1C1 and AKR1C2 explained why AKR1C2 inverted its stereospecificity from a 3alpha-HSD with 5alpha-DHT to a 3beta-HSD with tibolone. The preference for AKR1C1 and AKR1C2 to form 3beta-hydroxytibolone, and the preference of the liver-specific AKR1C4 to form 3alpha-hydroxytibolone, may explain why 3beta-hydroxytibolone is the major metabolite in human target tissues and why 3alpha-hydroxytibolone is the major circulating metabolite.

Effect of hormone therapy and raloxifene on serum VE-cadherin in postmenopausal women

To investigate the effect of continuous combined hormone therapy and raloxifene on serum VE-cadherin. The study was double blinded, with a placebo run-in period of 28-50 days. University menopause clinic. Twenty-eight healthy postmenopausal women devoid of climacteric complaints. Subjects were randomized to 17beta-estradiol (2 mg) + norethisterone acetate (1 mg; E(2)-NETA) or raloxifene hCL (60 mg) for a period of 6 months. Serum VE-cadherin, which was estimated at baseline and at month 6. Serum VE-cadherin decreased significantly in both E(2)-NETA and raloxifene groups (raloxifene baseline +/- SD: 1.17 +/- 0.44 ng/mL, 6 months: 0.82 +/- 0.29 ng/mL; E(2)-NETA baseline: 1.19 +/- 0.47 ng/mL, 6 months: 0.92 +/- 0.49 ng/mL). Percentage changes from baseline were -21.7 +/- 24.3 for E(2)-NETA and -26.0 +/- 20.6 for raloxifene. The effect of E(2)-NETA and raloxifene suggests that these drugs may preserve interendothelial junction integrity and control vascular permeability. Although this effect may influence the progress of the atheromatous lesion, its clinical impact on coronary artery disease (CAD) remains uncertain.

Hormone therapy after endometrial cancer.

Endometrial carcinoma is listed under the absolute contraindications to hormone therapy (HT). According to current opinion, HT after stage I or II is still considered an option, and continuous combined oestrogen/progestogen replacement therapy (CCEPT) would be recommended. However, up to now, only observational studies have been put forward. Although none of these studies have established an increased rate of recurrence or mortality, alternatives such as phytopreparations and tibolone, or particular psychotherapeutic drugs, such as venlafaxine, should be considered for the relief of climacteric complaints. Progestogen-only therapy (PT) particularly has been considered. However, the currently discussed possible progestogen effects regarding an increased risk of breast cancer have to be taken into account. Indeed, the wider discussion about the gestagen effects regarding the risk of breast cancer is to be considered. Generally, after hysterectomy, at least for patients with cardiovascular risk factors, the preference today is to use low-dose oestrogen therapy (patches or gels) instead of CCEPT, and this is also now recommended for patients after endometrial cancer. This is to be noted because of the risk factors for endometrial carcinoma, such as hypertension, obesity, polycystic ovary syndrome (PCO) and diabetes mellitus. However, each form of HT should be only exceptionally recommended, and the patients must be informed about the risks that exist and the use of alternatives.

Hormone Replacement Therapy, Selective Estrogen Receptor Modulators, and Tissue-Specific Compounds

In industrialized countries, coronary heart disease (CHD) is not only the leading cause of death in women but of disability as well. Menopause, regardless of age at onset, is associated with a marked increase in CHD risk. Based on epidemiologic studies demonstrating mainly positive biologic effects of hormone replacement therapy (HRT) on CHD risk factors and outcomes, earlier recommendations decreed that most, if not all, postmenopausal women should be treated with long-term HRT. Recent randomized controlled trials with clinical CHD endpoints have shown that previously held dicta may not be accurate. Selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene are alternatives to HRT. SERMs represent a growing class of compounds that act as either estrogen receptor agonists or antagonists in a tissue-selective manner. This pharmacologic profile may offer the opportunity to dissociate favorable cardiovascular effects of estrogen from unfavorable stimulatory effects on the breast and endometrium. The only data available regarding the effects of tamoxifen on cardiovascular events in postmenopausal women are from breast cancer trials. They showed fewer fatal myocardial events in women randomly assigned to tamoxifen compared with women assigned to placebo. Raloxifene is a so-called second-generation SERM. It seems clear that raloxifene increases bone mineral density, has no effect on the endometrium, and holds high promise for the prevention of breast cancer. The effect of raloxifene on cardiovascular disease is uncertain. On the basis of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene may offer some protection to women with cardiovascular disease or to those who are at high risk. Proof that raloxifene reduces the risk of CHD requires a clinical trial with hard clinical endpoints. Such a study is currently underway. Clinical trials have demonstrated that the synthetic 19-nortestosterone derivative tibolone reduces climacteric complaints and prevent osteoporosis without causing menstrual bleeding. Tibolone lowers lipoprotein(a), fibrinogen, and plasminogen activator inhibitor-1 levels and improves glucose tolerance, insulin sensitivity, and endothelial function; however, it also lowers high-density lipoprotein cholesterol by >20%. The long-term impact of tibolone on the risk of CHD is not known and needs to be studied.

Compliance with hormone replacement therapy at Songklanagarind Hospital.

To determine compliance with hormone replacement therapy (HRT) over a 2-year period, reasons for discontinuing HRT and the factors associated with non-compliance. A total of 202 women attending the menopause clinic at Songklanagarind Hospital and taking HRT were included in this retrospective study. Compliance was assessed for each 6-month interval within the first 2 years. Reasons for discontinuation were requested from women who had stopped using HRT. Compliance rates with HRT for the study group were 57.9% at 6 months, 42.6% at 12 months, 35.1% at 18 months and 32.7% at 24 months. The main reasons for discontinuing HRT were improvement of climacteric symptoms (20.9%), fear of cancer (16.4%) and irregular bleeding (11.9%). Logistic regression analysis revealed a significant increase in the risk of non-compliance of HRT among agriculturists or untrained workers (OR 4.7, 95% CI 1.2-18.8; reference, government employees), those with delayed onset of treatment (>1 years; OR 3.0, 95% CI 1.1-8.0; reference, 0-3 months) and those prescribed HRT for climacteric symptoms or reasons other than oophorectomy or ovarian failure (OR 18.2-41.6 depending on reasons). Agriculturists or untrained workers who delayed onset of treatment for climacteric symptoms had the highest expected non-compliance rate of 0.95%. Long-term compliance of HRT was not good at Songklanagarind menopause clinic. More attention has to be paid to the counseling of patients about HRT. Agricultural or untrained workers, late starting HRT, and presence of climacteric complaints were the significant factors for poor HRT compliance.

Sympathetic skin response in women receiving hormone replacement therapy

The peripheral skin sympathetic nerve function is continuously hyperstimulated in women with climacteric complaints, and one study concluded that, although the reason is not clear, sympathetic nerve dysfunction must be the main cause for this hyperstimulation w1x. Postmenopausal hormone replacement therapy (HRT) has significant effects on the amplitude of sympathetic skin response (SSR), but no significant effects on latency values. Another study concluded that estrogens have a significant inhibitory effect on the sympathetic neuron pool at the spinal cord level w2x. The present study investigated the effects of HRT on SSR. Forty-one postmenopausal women admitted to our menopause clinic were enrolled in the study. Women with heart failure, ischemic cardiopathy, chronic renal failure, severe hypertension, diabetes mellitus, or other disorders that might affect the autonomic nervous system were excluded. All women had hot flushes and sweating complaints. Before initiation of HRT, SRR tests were

Effect of hormone replacement therapy and tibolone on serum total homocysteine levels in postmenopausal women

Objective: To assess the effect of continuous combined hormone replacement therapy (HRT) or tibolone on serum total homocysteine (tHcy) levels in postmenopausal women. Study design: Ninety-five postmenopausal women aged 41–68 years were included in the study. Seventy-three women with climacteric complaints, osteopenia or osteoporosis received either conjugated equine estrogens 0.625 mg combined with medroxyprogesterone acetate 5 mg (CEE/MPA, n=31) or tibolone 2.5 mg ( n=42). Twenty-two healthy women, matched for chronological and menopausal age, served as controls. Serum tHcy levels were assessed at baseline, 6, 12 and 18 months. Results: No difference was recorded between groups regarding demographic characteristics or mean baseline serum tHcy. Serum tHcy levels decreased significantly in the CEE/MPA compared to baseline (change at 18 months: −3.9%, P<0.05). The magnitude of the decrease was higher in the subgroup of women with baseline tHcy levels above the median (change at 18 months: −15.0%, P<0.01). No change in tHcy levels was detected in the tibolone group throughout the study period, either in the whole group (change at 18 months: 1.9%, NS) or in the subgroup with baseline tHcy levels above the median (change at 18 months: −3.23%, NS). Conclusion: Continuous CEE/MPA reduces tHcy especially in women with high pretreatment tHcy levels. Tibolone has no effect on serum tHcy levels at least during the first 18 months of therapy. Larger studies with longer follow-up are required to confirm these results.

Effects of estradiol, cyproterone acetate, tibolone and raloxifene on uterus and aorta atherosclerosis in oophorectomized cholesterol-fed rabbits

Background: Different hormonal replacement regimens are used for treating climacteric complaints; however, not all of them have the same clinical profile. Cardiovascular disease (CVD) is a major health problem and tibolone, raloxifene, estradiol (alone or with cyproterone acetate) have been added to cholesterol-fed rabbits to study atherosclerosis. Methods: A total of 48 cholesterol-fed New Zealand white rabbits were studied for 4 months. Forty rabbits underwent bilateral ovariectomy and the other eight were sham operated (group S). The ovariectomized rabbits were allocated to five groups of eight animals each receiving tibolone (Group T, 6 mg/day), raloxifene (R, 35 mg/day), estradiol valerate (E, 3 mg/day), estradiol valerate plus cyproterone acetate (EC, 3+0.5 mg/day, respectively), and no treatment for the control group (C). The sham group received no treatment too. Results: After 4 months the percentage of the extent of atherosclerosis in the aorta was 30.4% in C group, 24.5% in S group, 10.2% in T group, 30.3% in R group, 17.9% in E group and 28.1% in EC group ( P<0.05 T vs. C, R, EC). The aortic cholesterol content compared with aortic weight was 8.55 μg/mg in C group, 11.97 μg/mg in S group, 1.86 μg/mg in T group, 3.82 μg/mg in R group, 2.86 μg/mg in E group and 5.24 μg/mg in EC group ( P<0.05 T vs. EC, C, S; R vs. C, S; E vs. C, S). Uterine weights in grams were: 1.89 (C group), 2.24 (S), 7.38 (T), 1.94 (R), 9.92 (E), and 5.94 (EC); P<0.05 (C, S, R, vs. T, E, EC; T vs. E; EC vs. T, E). Conclusion: Our study showed a decrease in the extent of aortic atherosclerosis in oophorectomized cholesterol-fed rabbits treated with tibolone or estradiol, and a decrease in aortic cholesterol content in rabbits treated with tibolone, raloxifene and estradiol. However, rabbits treated with tibolone showed an increased uterine weight, which is contrary to that observed in humans.

Cimicifuga extract BNO 1055: reduction of hot flushes and hints on antidepressant activity

Ethanolic- and isopropanolic-aqueous extracts of Cimicifuga racemosa are used for the treatment of climacteric complaints. As hot flushes and psychic complaints seem to be special targets for Cimicifuga extracts in clinical studies, these parameters were studied in experimental animals. Hot flush equivalents were measured in castrated rats as a quick increase in peripheral temperature with the aid of a transmitter implanted subcutaneously on the ventral side. The hot flush equivalents proved to respond to estrogen and the antidopaminergic drug veralipride but they were also reduced very effectively by Cimicifuga extract BNO 1055 (which is contained in Klimadynon®/Menofem®). In addition, an ethanolic-aqueous extract of C. racemosa was studied in the tail suspension test (TST), a behavioural test indicative for antidepressant activity. A significant decrease of the period of immobility was observed after treatment with 30 mg/kg body weight (bw) imipramine or with 50 or 100 mg/kg bw Cimicifuga extract. These findings in pharmacological tests—a reduction of the frequency of hot flush equivalents and hints on antidepressant activity of Cimicifuga extracts—are in good agreement with the therapeutical responses in climacteric women.

Phytoestrogens: endocrine disrupters or replacement for hormone replacement therapy?

Objectives: This review presents findings with clear statements from the literature as well as own results of effects of soy, red clover and their isoflavones as well as of the Cimicifuga racemosa extract BNO 1055. Experimental and clinical effects on climacteric complaints, osteoprotective effects, activity in the urogenital tract, and risks concerning cardiovascular diseases and mammary and endometrial tissue will be compared, also in comparison to classical hormone preparations. The question whether soy and red clover products and/or Cimicifuga racemosa (CR) preparations are endocrine disrupters or may fulfill the criteria of the so-called phyto-SERMs will be discussed. Methods: Review of selected publications since 1980 and summary of unpublished own results of the authors. Results: Experimental and clinical evidences suggest that soy/red clover and their isoflavones do not fulfill the criteria of an ideal SERM. They appear to have mild osteoprotective effects but do not improve climacteric complaints. Furthermore, they seem to stimulate uterine growth and mammary epithelial proliferation. In ovariectomized rats, the CR extract BNO 1055 showed many of the beneficial effects of 17β-estradiol, including effects in the brain/hypothalamus to reduce serum LH levels, effects in the bone to prevent osteoporosis and estrogenic effects in the urinary bladder. The CR extract BNO 1055 had no uterotrophic effect. Conclusion: If clinical studies confirm these results, the Cimicifuga racemosa preparation BNO 1055 would appear as an ideal SERM and may therefore be an alternative to hormone replacement therapy.

In vitro effects of the Cimicifuga racemosa extract BNO 1055

Objectives: Extracts of Black cohosh ( Cimicifuga racemosa or CR) have been used for the treatment of climacteric complaints since decades. Efficacy, particularly concerning neurovegetative and psychic symptoms, has been proven in clinical trials. As active principle yet unknown substances with selective estrogen receptor modulator (SERM) activity are assumed. Recently, evidence arose that CR may also contain dopaminergic compounds, which may contribute to the therapeutic activity of the extract. Methods: Two subtypes of the estrogen receptor (ERα and ERβ) are known. To examine, whether active substances of CR extract BNO 1055 (which is contained in Klimadynon® and Menofem®) bind to either of the two estrogen receptors, subtype-specific estrogen receptor ligand-binding assays with recombinant ERα or ERβ were conducted. A ligand-binding assay with recombinant dopamine D 2-receptor protein was employed to assess possible dopaminergic activity in the CR extract BNO 1055. Results: While a displacement of radiolabeled estradiol from binding sites of a cytosol preparation from procine and human endometrium by CR extract BNO 1055 was shown no such displacement was achieved when either ERα or ERβ protein was used as ligands for tracer. Dopaminergic activity in the CR extract BNO 1055 could be demonstrated with the D 2-receptor assay. A countercurrent chromatography resulted in a separation of estrogenic and dopaminergic activity in two distinct fractions. Conclusions: It is suggested that not yet identified substances in the CR extract BNO 1055 bind to a yet unknown estrogen-binding site in the endometrium. Also, yet unknown dopaminergic compounds may contribute to the pharmacological profile of CR extract BNO 1055.