Dana Seidlova-Wuttke

The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers

OBJECTIVES In the present study, therapeutic effects of the Cimicifuga racemosa preparation CR BNO 1055 (Klimadynon/Menofem) on climacteric complaints, bone metabolism and endometrium will be compared with those of conjugated estrogens (CE) and placebo. The question whether CR BNO 1055 contains substances with selective estrogen receptor modulator (SERM) activity will be investigated. METHODS Sixty-two evaluable postmenopausal women were included in the double-blind, randomized, multicentre study, and treated either with CR BNO 1055 (daily dose corresponding to 40 mg herbal drug), 0.6 mg CE, or matching placebo, for 3 months. Menopausal symptoms were assessed by the menopause rating scale (MRS) and a diary. Levels of CrossLaps (marker of bone degradation) were determined by ELECSYS system and bone-specific alkaline phosphatase (marker of bone formation) by an enzymatic assay. Endometrial thickness was measured via transvaginal ultrasound; vaginal cytology was also studied. The primary efficacy criterion was the change from baseline to end point in the MRS. Change from baseline was analyzed for the secondary variables too. RESULTS CR BNO 1055 proved to be equipotent to CE and superior to placebo in reducing climacteric complaints. Under both verum preparations, beneficial effects on bone metabolism have been observed in the serum. CR BNO 1055 had no effect on endometrial thickness, which was significantly increased by CE. Vaginal superficial cells were increased under CE and CR BNO 1055 treatment. CONCLUSION The results concerning climacteric complaints and on bone metabolism indicate an equipotent effect of CR BNO 1055 in comparison to 0.6 mg CE per day. It is proposed that CR BNO 1055 contains substances with SERM activity, i.e. with desired effects in the brain/hypothalamus, in the bone and in the vagina, but without exerting uterotrophic effects.

Chaste tree (Vitex agnus-castus)--pharmacology and clinical indications.

Extracts of the fruits of chaste tree (Vitex agnus castus = AC) are widely used to treat premenstrual symptoms. Double-blind placebo-controlled studies indicate that one of the most common premenstrual symptoms, i.e. premenstrual mastodynia (mastalgia) is beneficially influenced by an AC extract. In addition, numerous less rigidly controlled studies indicate that AC extracts have also beneficial effects on other psychic and somatic symptoms of the PMS. Premenstrual mastodynia is most likely due to a latent hyperprolactinemia, i.e. patients release more than physiologic amounts of prolactin in response to stressful situations and during deep sleep phases which appear to stimulate the mammary gland. Premenstrually this unphysiological prolactin release is so high that the serum prolactin levels often approach heights which are misinterpreted as prolactinomas. Since AC extracts were shown to have beneficial effects on premenstrual mastodynia serum prolactin levels in such patients were also studied in one double-blind, placebo-controlled clinical study. Serum prolactin levels were indeed reduced in the patients treated with the extract. The search for the prolactin-suppressive principle(s) yielded a number of compounds with dopaminergic properties: they bound to recombinant DA2-receptor protein and suppressed prolactin release from cultivated lactotrophs as well as in animal experiments. The search for the chemical identity of the dopaminergic compounds resulted in isolation of a number of diterpenes of which some clerodadienols were most important for the prolactin-suppressive effects. They were almost identical in their prolactin-suppressive properties than dopamine itself. Hence, it is concluded that dopaminergic compounds present in Vitex agnus castus are clinically the important compounds which improve premenstrual mastodynia and possibly also other symptoms of the premenstrual syndrome.

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 17beta-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.

Standardized Bending and Breaking Test for the Normal and Osteoporotic Metaphyseal Tibias of the Rat: Effect of Estradiol, Testosterone, and Raloxifene

The fracture of bone plays a key role in osteoporosis. BMD measurement, however, is only an indirect parameter of this phenomenon. We therefore developed a highly sensitive three‐point bending test for the metaphyseal tibias in rats to evaluate stiffness and strength. This was validated in a right‐left comparison and a bioassay with soy‐free food, estradiol, raloxifene, and testosterone in orchidectomized rats.

Endocrine disruptors and the thyroid gland--a combined in vitro and in vivo analysis of potential new biomarkers.

Background There is growing evidence that, in addition to the reproductive system, the hypothalamic–pituitary–thyroid axis is a target of endocrine-disrupting compounds (EDCs). However, this is not reflected adequately in current screening and assessment procedures for endocrine activity that to date determine only general parameters of thyroid function. Objective and Methods We used several in vitro and ex vivo assays in an attempt to identify suitable biomarkers for antithyroid action testing a selected panel of putative EDCs. Results In vitro we detected stimulation or inhibition of iodide uptake into FRTL-5 rat thyroid cells, inhibition of thyroid hormone binding to transthyretin, agonistic or antagonistic effects in a thyroid hormone receptor–dependent reporter assay, and inhibition of thyroid peroxidase using a novel assay system based on human recombinant thyroperoxidase that might be suitable for routine screening for potential EDCs. In rats, chronic application of several EDCs led to changes in thyroid morphology, alterations of thyrotropin and thyroid hormone serum levels as well as alterations in peripheral thyroid hormone–regulated end points such as malic enzyme and type I 5′-deiodinase activity. Conclusions As the effects of EDCs do not reflect classic mechanisms of hormone-dependent regulation and feedback, we believe multitarget and multimodal actions of EDCs affect the hypothalamic–pituitary–thyroid axis. These complex effects require a diverse approach for screening, evaluation, and risk assessment of potential antithyroid compounds. This approach involves novel in vitro or cell-based screening assays in order to assess thyroid hormone synthesis, transport, metabolism, and action as well as in vivo assays to measure thyroid hormone–regulated tissue-specific and developmental end points in animals.

Pharmacology of Cimicifuga racemosa extract BNO 1055 in rats: bone, fat and uterus

OBJECTIVES Hormone replacement therapy (HRT) has therapeutic effects on climacteric complaints and prevents osteoporosis. Owing to the increased risks of breast cancer and cardiovascular diseases, patients look for alternatives. Cimicifuga racemosa (CR) preparations might be an alternative, because they proved to reduce climacteric complaints as efficiently as conjugated estrogens without exerting estrogenic effects in the uterus. Whether CR has positive effects on bone and in fat tissue is currently unknown. Therefore, osteoprotective effects of the CR extract BNO 1055 and an influence on fat tissue were studied in ovariectomized rats. METHODS Bone mineral density (BMD) of the tibia of ovariectomized (ovx) rats was determined by computer-assisted tomography (CT). CT scans of fat depots were perimetrically quantified. Bone turnover (osteocalcin, crosslaps) and lipocyte activity (leptin) were also determined. Uterine weights were measured and gene expression of estrogen-regulated uterine genes (IGF-1, ERbeta) was determined by RT-PCR. RESULTS Treatment of the ovx rats over a period of 3 months with E(2) and the CR extract BNO 1055 showed osteoprotective effects; both significantly reduced the loss of BMD in tibia. Serum osteocalcin levels were significantly reduced by both treatments, whereas only E(2), but not BNO 1055, reduced serum crosslaps. A paratibial fat depot and serum leptin concentration were also significantly reduced. In contrast to E(2), the CR extract showed no effect on uterine weight and gene expression of E(2)-regulated genes. CONCLUSION The CR extract BNO 1055 exerted estrogenic effects in the bone (particularly in osteoblasts) and in fat tissue, but not in the uterus of ovx rats. The extract appears to contain rat organ-specific selective estrogen receptor modulators (SERMs), and if these findings can be approved in human it may be an alternative to HRT.

Estrogen and raloxifene improve metaphyseal fracture healing in the early phase of osteoporosis. A new fracture-healing model at the tibia in rat

BackgroundFracture healing in osteoporosis is delayed. Quality and speed of fracture healing in osteoporotic fractures are crucial with regard to the outcome of patients. The question arises whether established antiosteoporotic drugs can further improve fracture healing.Materials and methodsOsteoporosis manifests predominantly in the metaphyseal bone. Nevertheless, an established metaphyseal fracture model is lacking. A standardized metaphyseal fracture-healing model with stable plate fixation was developed for rat tibiae. The healing process was analyzed by biomechanical, gene expression, and histomorphometric methods in ovariectomized (OVX) and sham-operated rats (SHAM), compared to standardized estrogen (E)- and raloxifene (R)-supplemented diets.ResultsEstrogen and raloxifene improved the biomechanical properties of bone healing compared to OVX (Yield load:

Contribution of a Membrane Estrogen Receptor to the Estrogenic Regulation of Body Temperature and Energy Homeostasis

{\text{SHAM}} = 63.1 \pm 20.8{\text{N}}