Maturitas

Published by Elsevier
Online ISSN: 0378-5122
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Article
The aim of the study was to confirm the superior efficacy of estriol containing pessaries compared to placebo in the treatment of vaginal atrophy. In a prospective, multicenter, randomized, placebo-controlled, double-blind study, 436 postmenopausal women with vaginal atrophy (vaginal maturation index, VMI<40%; vaginal pH>5; most bothersome symptom, MBS≥65 on visual analogue scale, VAS) were treated with pessaries containing either 0.2mg estriol (N=142) or 0.03mg estriol (N=147) or with a matching placebo (N=147) for 12 weeks. Primary efficacy endpoints included increase in VMI, decrease of the vaginal pH value and decrease in intensity of MBS after 12 weeks of treatment. The increase in VMI was significantly greater under 0.2mg estriol and 0.03mg estriol (46.3±17.0 and 38.4±19.4, respectively) compared to placebo (23.9±21.5; p values<0.001), vaginal pH decreased significantly more (-1.6±0.8 and -1.4±0.9, respectively) compared to placebo (-0.6±0.8; p values<0.001) and MBS intensity (VAS) declined significantly more (-52.2±23.7 and -47.1±23.4, respectively) compared to placebo (-31.8±26.3; p values<0.001). Adverse events were rare and occurred at similar rates in all three groups. Superiority of estriol containing pessaries over placebo was shown in the local treatment of vaginal atrophy. Even a very low dose of 0.03mg estriol proved sufficient for local treatment of vaginal atrophy with excellent tolerability.
 
Article
Estrogen or combined hormone (estrogen-progestin) therapy is highly efficacious for managing the signs and symptoms of urogenital atrophy. A low, effective estrogen dose may enhance patient acceptance and reduce side effects. In this randomized, double-blind, multicenter clinical trial, 71 healthy postmenopausal women with vaginal atrophy (Vaginal Maturation Index < or =55) received either low-dose synthetic conjugated estrogens, A tablets (Cenestin) (SCE-A), 0.3 mg once daily, or placebo for 16 weeks. Treatment with SCE-A for 16 weeks resulted in a highly significant (P<0.0001) mean increase of 17.7 in the Vaginal Maturation Index compared to a mean increase of 4.1 with placebo treatment. A significant estrogenic improvement was detected as early as 4 weeks (mean increase 14.6). Superficial cells were significantly increased from 2.1% at baseline to 15.9% at week 16 with SCE-A, and parabasal cells were significantly reduced from 23.0% at baseline to 1.6% at week 16 (P<0.01 between treatments for both). Vaginal pH was significantly decreased from 6.2 at week -2 to 5.2 at week 16 with SCE-A compared to placebo (P<0.0001). There were no significant differences between treatment groups in the incidence of treatment-emergent side effects or other measures of safety, except for urinary tract infection, which occurred more frequently in the placebo group. These results confirm the relatively rapid estrogenic effect and safety of a low-dose (0.3 mg/day) of slow-release SCE-A (Cenestin) in the treatment of vaginal atrophy in postmenopausal women.
 
Article
Guidelines recommend using the lowest effective dose of oestrogen for the management of vasomotor symptoms in postmenopausal women. The primary aim of this double-blind, multi-centre, randomised study was to assess the efficacy of oral ultra-low dose continuous combined hormone replacement therapy with 17β-oestradiol and dydrogesterone. 313 women with ≥50 moderate to severe hot flushes during the previous week were randomised to 0.5 mg 17β-oestradiol/2.5 mg dydrogesterone (E 0.5 mg/D 2.5 mg), 1mg 17β-oestradiol/5mg dydrogesterone (E 1mg/D 5 mg) or placebo for 13 weeks. The placebo group then switched to E 0.5 mg/D 2.5 mg for a further 39 weeks, whilst the other groups continued on the same treatment. After 13 weeks, the reduction in the number of moderate to severe hot flushes/day in the E 0.5 mg/D 2.5 mg group was greater than in the placebo group (-6.4 vs. -4.9, p<0.001) and comparable to that in the 1/5 mg group (-6.3). E 0.5 mg/D 2.5 mg and E 1mg/D 5 mg significantly improved the total Menopause Rating Scale score. The number of bleeding/spotting days was lower with E 0.5 mg/D 2.5 mg than with E 1 mg/D 5 mg. The overall amenorrhoea rate with E 0.5 mg/D 2.5 mg was 81%; this increased to 91% in months 10-12. Continuous combined 0.5 mg 17β-oestradiol and 2.5mg dydrogesterone was effective in alleviating vasomotor symptoms and improving quality of life, and was associated with a high amenorrhoea rate and a good tolerability profile.
 
Article
to compare the patterns of a 17 beta-estradiol (E(2)) gel containing 0.6 mg/g (1.5 mg E(2) per day, Gelestra); with the transdermal delivery system (Estraderm TTS 50) applied every 3 days over a 14-day period to women in spontaneous or surgical menopause. a single centre, open, randomised, parallel-group study was conducted. A total number of 33 postmenopausal women were enrolled. In 23 of them the menopause occurred spontaneously, while 10 women were bilaterally ovariectomized. Randomly, the subjects were treated with Estraderm TTS 50 (no. 8) or with Gelestra (no. 14). The pharmacokinetic study of the drugs was performed at the seventh, ninth and 14th day in Gelestra treated women and at the first, third and second day in Estraderm TTS 50 treated women. In fact, the seventh, ninth and 14th day of percutaneous treatment corresponds to the first, third and second day of application of the transdermal system application. Blood samples were taken by each subject at baseline and 1, 2, 3, 4, 8, 12 and 24 h after the gel or transdermal system application. In almost all samples the level of E(2) and estrone (E(1)) were evaluated. Statistical analysis was performed by comparing the two groups of treatment. The following parameters were assessed: mean E(2) and E(1) concentrations, E(2) peak serum concentration within interval from 0 to 72 h (C(max)), E(2) trough concentration within interval from 0 to 72 h (C(min)), area under the E(2) time concentration curve in the interval from 0 to 72 h (AUC((0-72))), the average E(2) concentration during the measurement interval, calculated by dividing AUC((0-72)) by 72 h (C(av)), E(1)/E(2) ratio, and percentage fluctuation (%Fluct) which is equal to 100 (C(max)-C(min)/C(max)). there was no significant difference in E(2) C(av) between the two treatments. However, significant differences in favour to the gel on the first day (first h) and on third day (72nd h) and in favour to the patch at the second day (48th h) were detected. C(max), E(1)/E(2) ratio and AUC((0-72)) were not statistically different, while a significantly higher C(min) for the gel was observed. Furthermore, the 90% confidence interval for AUC((0-72)) ratio (0.83-1.10) was within the commonly applied bioequivalence acceptance range (0.80-1.25). The %Fluct was significantly lower for Gelestra than for Estraderm TTS 50. although the mean E(2) and E(1)concentrations, C(max), E(1)/E(2) ratio and the AUC((0-72)) did not differ between the two E(2) treatments, the Gelestra treatment showed a lower day-to-day variation over the three day application, than the Estraderm TTS 50.
 
Article
The prevalence of fractures in women aged 45-86 years resident in the city of Gothenburg, Sweden, was investigated by means of a postal questionnaire. A sample of 10,000 women from seven birth cohorts (1900-1940) was obtained at random from the population register. The response rate was 70.1% in the 1900-1920 and 81.0% in the 1930 and 1940 birth cohorts. When the prevalence of fractures sustained between 25 and 46 years of age was analyzed a higher figure emerged for women from the 1930 and 1940 birth cohorts than for those from the 1900-1920 cohorts, indicating an increasing incidence of fractures over time. There was a significant independent correlation between early menopausal age and a high rate of fractures. Menopausal age decreased with increasing tobacco consumption. There was also a significant independent correlation between tobacco-smoking and a high fracture rate. The prevalence of tobacco-smoking increased from 30.0 to 38.1% between the 1930 and 1940 birth cohorts, which may further increase the fracture risk in future years. Despite increasing vitality and longevity among the elderly in Gothenburg, there are indications that the number of fractures will increase in the future.
 
Article
We have previously shown that OS-0689 attenuates the rise in tail skin temperature of ovariectomized rats, which is believed to be relevant to human symptoms of hot flush. In this study, we elucidate the mechanism underlying the ameliorating effects of OS-0689 on elevated tail skin temperature. Female Sprague-Dawley rats were ovariectomized and orally treated with OS-0544 (1 mg/kg), OS-0689 (3 mg/kg; (+)-enantiomer of OS-0544) or 17beta-estradiol (3 mg/kg; E2) for 1 week. At 1, 3 or 6 weeks after ovariectomy, the vasoconstrictions and vasorelaxations induced by periarterial nerve stimulation (PNS), l-noradrenaline (NA), and rat calcitonin gene-related peptide (CGRP) in isolated tail arteries were compared between OVX and sham-operated rats. Three weeks after ovariectomy, vasoconstrictions in response to PNS and NA in the arteries of OVX rats were markedly less than those in the arteries of sham-operated rats. However, at 1 and 6 weeks after ovariectomy the stimuli-induced vasoconstrictions in the arteries of OVX rats were greater than those of sham-operated rats. Moreover, NA reactivity was not attenuated in the mesenteric arteries at 3 weeks after ovariectomy. OS-0544, OS-0689 and E2 prevented the decrease in vasoconstrictions in the tail arteries. Vasorelaxations in response to PNS and rat CGRP were significantly greater in the arteries of OVX rats than in those of the sham-operated rats. OS-0689 inhibited the increase in vasorelaxation induced by both stimuli, whereas E2 had no effects. Ovariectomy not only decreases adrenergic function but also enhances CGRPergic function in rats' tail arteries. OS-0689 improves both impairments and thereby improves on rat hot flush.
 
Article
Most hip fractures occur in subjects without osteoporosis and are associated with a fall. Conventional menopausal hormone therapy (HT) improves postural balance, which might explain the rapid reduction in hip fracture risk. It is unclear whether tibolone improves postural balance, which might determine its effects on peripheral fracture risk. To study the short-term effects of low-dose tibolone therapy on postural balance in elderly women. Eighty healthy women (70 evaluable), aged 60 years or more, were recruited through advertising in the local media. They were randomly allocated to receive either tibolone (1.25 mg/d) or placebo for 6 months. Postural balance was assessed as sway velocity, using a force platform. Baseline characteristics, including serum estradiol values and postural balance, were similar in the two study groups. On average, the overall dosing compliance was very high, over 97% in both groups. After 6 months, sway velocity had decreased (improved) by 7.6% (-0.97 cm/s; P=0.16 vs. baseline) in the tibolone arm and by 2.5% (-0.30 cm/s; P=0.59 vs. baseline) in the placebo group. The difference 0.67 cm/s was not statistically significant (95% CI -2.44, 1.10; P=0.45). Adjustments for age, serum estradiol level and variable value at baseline, revealed similar results. Short-term treatment with tibolone (1.25 mg/d), compared to placebo, did not significantly affect postural balance function in elderly women.
 
Article
To assess the effects of bazedoxifene/conjugated estrogens (BZA/CE) on sleep parameters and health-related quality of life (HR-QOL). This was a 12-week, multicenter, double-blind, placebo-controlled phase 3 study. Postmenopausal women with an intact uterus and experiencing >or=7 moderate-to-severe hot flushes daily were randomized to BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg, or placebo. In these secondary efficacy analyses, the Medical Outcomes Study (MOS) sleep scale and Menopause-Specific Quality of Life (MENQOL) questionnaires and the Menopause Symptoms Treatment Satisfaction Questionnaire (MS-TSQ) evaluated measures of sleep, menopausal symptoms, and satisfaction with treatment, respectively. A total of 318 subjects (mean age, 53.4 years) received >or=1 dose of study drug. At Week 12, BZA 20 mg/CE 0.45 and 0.625 mg showed significant improvements over placebo in the MOS sleep scale for time to fall asleep, sleep adequacy, sleep disturbance, and sleep problems indexes I and II (P<0.001). A reduction in hot flush frequency was significantly associated with improvement in sleep parameters (P<0.05) based on linear regression and responder analyses. Both BZA/CE doses showed significantly greater improvements over placebo in vasomotor function and total MENQOL score (P<0.001). Results of the MS-TSQ showed that subjects treated with BZA/CE versus placebo reported significantly greater overall satisfaction with treatment (P<0.05), as well as greater satisfaction with sleep quality, ability to control hot flushes during the day and night, effect on mood/emotions, and tolerability. Symptomatic postmenopausal women treated with BZA/CE experienced significant improvements in sleep parameters and overall HR-QOL.
 
Article
This paper reports the cause, incidence of malignancies, certain clinical features, and the time lag between the bleeding and the establishment of its cause, in the 1019 cases of post-menopausal bleeding investigated by the Universitäts-Frauenklinik in Tübingen, West Germany, between 1969 and 1972. Although many of the patients had experienced just one post-menopausal bleeding before seeking medical help, and most reported that their bleeding(s) had been "light" and of short duration, a malignancy was found in 48% of the cases. The most common were cervical cancer (228 cases) and endometrial cancer (215). 31% of the cervical cancers and 12% of the endometrial cancers were in an advanced stage of development. A clear link emerged between increased age and the incidence of malignancies, but the paper shows the importance of any type of post-menopausal bleeding, however slight, being thoroughly investigated.
 
Article
The hypothesis was that the calcium and vitamin D supplementation prevents falls at the population level.Study design: The OSTPRE-FPS was a randomized population-based open-trial with 3-year follow-up. The supplementation group (n=1566) received daily cholecalciferol 800IU+calcium carbonate 1000mg, while the control group (n=1573) received no supplementation or placebo. A randomly selected subsample of 593 subjects underwent a detailed measurement program including serum 25(OH)D measurements. The occurrence of falls was the primary outcome of the study. The participants in the subsample were telephoned at 4 months intervals and the rest of the trial population was interviewed by phone once a year. In the entire trial population (ETP), there were 812 women with 1832 falls in the intervention group and 833 women with 1944 falls in the control group (risk ratio was 0.98, 95% CI 0.92-1.05, P=0.160). The supplementation was not associated with single or multiple falls in the ETP. However, in the subsample, multiple fall incidence decreased by 30% (odds ratio (OR) 0.70, 95% CI 0.50-0.97, P=0.034) in the supplementation group. Further, the supplementation decreased the incidence of multiple falls requiring medical attention (OR 0.72, 95% CI 0.53-0.97, P=0.031) in the ETP. The mean compliance in the entire trial population was 78% and in the subsample 79%. Overall, the primary analysis showed no association between calcium and vitamin D supplementation and risk of falls. However, the results of a post hoc analysis suggested that there was a decreased risk of multiple falls requiring medical attention: this finding requires confirmation.
 
Article
Cette etude a ete effectuee a partir des resultats d'un questionnaire adresse a des femmes de Bandung appartenant a de nombreux clubs et organisations feminines, cet echantillonnage n'est donc pas vraiment representatif ni du pays, ni de la region mais seulement d'un groupe socioculturel de Bandung
 
Article
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. 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. 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. 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.
 
Article
For Cimicifuga racemosa, well-founded investigations concerning multiplication, germination of seeds and field cultivation have not yet been published. Defined origins or varieties with certain agronomic properties and a specific pattern of active compounds are not commercially available. Special challenges are found with regard to growing of young plantlets from seeds. Comprehensive investigations have been started to find optimal conditions for all steps of the whole process to establish cultivation for Cimicifuga. Aim is to get defined varieties or sources with desirable agronomic characteristics and specific reproducible compound patterns in order to reach homogeneous plant raw material. For analytical tests, validated HPLC and TLC methods were used. Results from germination experiments with different temperature regimens show that the time for germination can be shortened from about 20 months to about 6 months. Gibberellic acid had positive influence on the development of the embryo. Content of triterpenglycosides and phenolic compounds was highest in May and June and decreased then from July until September. The quality of the ethanolic extract BNO 1055 (contained in Klimadynon(R) and Menofem(R)) differs from that of an isopropanolic extract. Comparison was carried out by means of TLC pattern of triterpenglycosides and phenolic compounds. Extensive systematic research on cultivation parameters with regard to all stages from the seeds to the herbal drug enables commercial field cultivation of Cimicifuga. Controlled cultivation (according to good agricultural practice or GAP) ensures the availability of homogenous standardized raw material. For pharmacological and clinical studies, standardized extracts and finished herbal medicinal products are required. Results of these studies are never transferable to other products and therefore valid only for the tested extracts/products.
 
Article
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.
 
Article
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. Two subtypes of the estrogen receptor (ERalpha and ERbeta) 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 ERalpha or ERbeta 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. 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 ERalpha or ERbeta 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. 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.
 
Article
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. 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. 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. 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.
 
Article
Estrogens have a profound influence on skin. The hypoestrogenism occurring after the menopause leads to measured deterioration in the skin. Estrogen receptors have been identified in the skin and the concentration of these receptors varies in the different parts of the body. Estrogen improves skin in more than one way, the collagen content and quality is improved, skin thickness is increased, while vascularisation is enhanced. The extracellular matrix responsible for the tone and appearance of the skin is also improved. It is not just the skin that shows an improvement with estrogen therapy but also skin appendages, such as hair. Estrogens have been shown to increase the hair follicle life cycle. Skin aging is not totally estrogen dependent because the ravages of age and the external environment play very important roles. The effects of estrogen on skin need further elucidation and with the emergence of newer techniques it is now possible to study more clearly the changes occurring at the cellular level. Estrogen replacement reverses the deleterious effect of estrogen deprivation on the skin, which is thus yet another organ that benefits from hormone replacement therapy.
 
Article
To evaluate the efficacy of three doses of estrogen/progestin therapy for relief of vasomotor symptoms (VMS) and vaginal atrophy in Asian women of different ethnic background; to examine differences in prevalence of VMS among ethnic groups. A prospective, randomized, double-blind multinational clinical trial in healthy postmenopausal women from 11 Asian countries. Following 2 weeks of baseline observations, the women received one of three conjugated estrogens (CE)/medroxyprogesterone acetate (MPA) doses (in mg) daily for 24 weeks: 0.625/2.5; 0.45/1.5; or 0.3/1.5. The women recorded VMS and uterine bleeding daily on diary cards translated into 10 languages. Vaginal responsiveness was evaluated by the vaginal maturation index (VMI) at baseline and at week 24. The study population consisted of 1028 postmenopausal women. The VMS-evaluable subpopulation was about 60% of the total population. The mean baseline hot flush frequency was 1.6 flushes/day (613 women). Hot flush frequency decreased significantly in all dose groups within 4 weeks of treatment. The VMI shifted significantly from immature (parabasal) to mature (superficial) cells at end of treatment. The therapeutic responses were comparable in all three groups. However, uterine bleeding was consistently less frequent in the 0.3/1.5 mg group. The percentage of women who reported VMS at baseline differed substantially among the different ethnic groups, ranging from 5% in Indonesian women to 100% in Vietnamese women. Asian postmenopausal women respond to CE/MPA therapy. The lowest dose is as effective for VMS and vaginal responsiveness as the higher doses, and the lowest dose is associated with the most favorable bleeding pattern. The prevalence of vasomotor symptoms differs among ethnic groups.
 
Article
Osteoprotegerin (OPG) inhibits osteoclast function by acting as a decoy receptor for receptor activator of nuclear factor-κB ligand (RANKL), thus being an important candidate gene for osteoporosis. Three recent genome-wide association studies also identified the TNFRSF11B gene, coding for OPG, as playing a key role in bone mineral density (BMD) regulation. As variations in the TNFRSF11B gene could alter the susceptibility to osteoporosis, the aim of study was to investigate association of two TNFRSF11B gene polymorphisms with BMD and serum OPG concentration in postmenopausal women. 478 postmenopausal women were genotyped for the presence of TNFRSF11B gene polymorphisms 245T > G (rs3134069) and 1181G > C (rs2073618). BMDs and serum OPG concentrations were measured. Two common haplotypes GT and CT occurred in 41.2% and 52.4% of subjects. In osteoporotic postmenopausal women, lumbar spine BMD was associated with polymorphisms 245T > G and 1181G > C, as well as with CT haplotype (p values 0.013, 0.006 and 0.006, respectively). Additionally, femoral neck BMD showed the association with 245T > G (p = 0.047). No other statistically significant associations with BMD were found for the studied SNPs and haplotypes. No association with serum OPG concentration was shown in any of the studied groups. Our results suggest that, in postmenopausal osteoporosis, polymorphisms 245T > G and 1181G > C, as well as haplotype CT in TNFRSF11B gene influence BMD.
 
Article
Selective estrogen receptor modulators (SERMs) are drugs that exhibit both estrogen agonistic and antagonistic effects that are tissue-specific. Ospemifene (FC-1271a) is a novel SERM compound, which has been shown in animal models to have estrogen-like effects on bone and the cardiovascular system, while having antiestrogen-like effects in uterus and breast. In this study, we investigated the effects of ospemifene on the uterine endometrium, vaginal maturation index and hormonal status in healthy postmenopausal women. The study was conducted as a double-blind, placebo-controlled phase I study, where 40 healthy postmenopausal women volunteers were randomized to receive daily oral doses of ospemifene either 25, 50, 100 or 200 mg or placebo for 12 weeks. Vaginal ultrasonography and endometrial biopsy were performed and vaginal maturation index determined at baseline and at 12 weeks' visit. Serum concentrations of estradiol, luteinizing hormone, follicle stimulating hormone (FSH), sex-hormone binding globulin (SHBG), parathyroid hormone and prolactin were determined from samples taken at baseline, at 4 days and at 4, 12, and 16 weeks' visits. Climacteric symptoms were assessed using 12 visual analogue scales (VAS) at baseline and at the end of the study. No clinically significant changes were seen in endometrial thickness at any dose level. Ospemifene exerted a very weak estrogenic effect on endometrial histology. On the other hand, it induced a clear estrogenic effect on vaginal epithelium. Among the endocrine parameters only FSH and SHBG showed significant dose dependent changes; FSH decreased and SHBG increased during the treatment. In general, ospemifene was well tolerated. The 25 and 50 mg doses tended to reduce climacteric symptoms, but no statistically significant differences were observed between different doses of ospemifene and placebo. The highest dose level (200 mg) induced more subjective adverse reactions, especially hot flushes, than lower doses. Our study suggests that a safe and well tolerated dose of ospemifene for potential clinical use may be between 25 and 100 mg. Further studies are needed to substantiate the results of this Phase I pilot study.
 
Article
The possible existence of an oestrus cycle dependent on local transfer of 133xenon from vagina to uterus was investigated in anaesthetized rats. 133Xenon in saline was infused into the vaginal lumen of rats in oestrous (n = 7) and dioestrous (n = 10). The uterus was removed 3 min after the infusion and the radioactivity in the organ counted, after which the remaining radioactivity in vagina was measured. The results showed that the radioactivity increased in all uteri compared with that of the background. The average transfer, expressed as per cent transfer, from vagina in the dioestrous group (5.5%) was significantly higher (P < 0.01, Mann-Whitney) than in the oestrous group (1.4%). The results suggest that the rate of transfer from vagina to uterus depended on the oestrous cycle. Vaginal treatment of women with progesterone for example, may similarly induce high local concentrations in the uterus. Empirically this is already used after in vitro fertilisation, it may also prevent progesterone induced migraine in menopausal women. The possible cycle dependent variations in the transfer in women should be evaluated.
 
Article
The effects of 8 weeks of daily oral treatment with 1 mg 17 beta-oestradiol (E2), 2.5 mg Org OD 14 [7 alpha, 17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one) , a steroid with weak androgenic, weak oestrogenic and weak progestational activity, or placebo on calcium and lipid metabolism were compared in 21 healthy, early post-menopausal women in a randomised double-blind study. The treatment period was followed by a treatment-free period of 8 weeks to study the reversibility of drug-induced effects. The results show that both E2 and Org OD 14 reduce bone resorption, as indicated by the decreases in the urinary hydroxyproline/creatinine and calcium/creatinine ratios in 2-h fasting urine. In contrast to E2, Org OD 14 did not reduce serum calcium levels. As regards lipid parameters, E2 reduced the concentration of serum cholesterol and Org OD 14 decreased serum levels of high-density-lipoprotein cholesterol and triglycerides. All these effects appeared to be reversible after cessation of treatment. It is concluded that both of these steroids reduce bone resorption in early post-menopausal women, but that their mechanisms of action are most likely different.
 
Article
To study the effect of Org OD 14 [17 alpha, 17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one) on the endometrium, 9 healthy post-menopausal women were given a daily dose of 2.5 mg of Org OD 14 for 100 consecutive days. In addition, during days 91-100 a daily oral dose of 1 mg of lynestrenol was taken by each volunteer. Endometrial biopsies were obtained before the start of treatment and on day 91. At pre-treatment, the endometrium was atrophic in 7 out of 9 volunteers and weakly stimulated in 2 volunteers. On day 91, the endometrium was found atrophic in 8 out of 9 volunteers and weakly stimulated in 1. Breakthrough bleeding occurred in 1 volunteer. After cessation of the combined treatment with Org OD 14 and lynestrenol, withdrawal bleeding occurred only in 1 volunteer. To assess the efficacy of Org OD 14 in the treatment of climacteric complaints a double-blind cross-over study was performed in 29 post-menopausal women. Patients were randomly allocated to Org OD 14 or to placebo as first treatment. Each period of treatment lasted 4 mth; no wash-out period was introduced. Patients took 1 Org OD 14 tablet (2.5 mg) or 1 placebo tablet per day. The patients scored hot flushes and sweating. At the end of the second treatment period, each patient was asked which of the 2 treatments she preferred. Data sufficient to allow for a conclusion were obtained from 20 patients.(ABSTRACT TRUNCATED AT 250 WORDS)
 
Article
The aim of the first part of this study was to evaluate the effects of a new synthetic steroid (7 alpha,17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (Org OD 14), on anterior pituitary (AP) and neurointermediate pituitary lobe (NIL) contents and on circulating levels of beta-endorphin (beta-EP) in rats. Three weeks after ovariectomy, groups of 9 rats were treated with either Org OD 14 (2 or 10 micrograms/day/rat for 14 days) or a placebo. In addition, 2 groups of ovariectomized rats were also treated with oestradiol benzoate (EB) (2 or 10 micrograms/day/rat for 14 days) to compare the effectiveness of the new steroid with that of a classical oestrogenic substance. beta-Ep concentrations were measured in plasma and in AP and NIL extracts by means of double-antibody radioimmunoassay (RIA), employing a specific anti-camel beta-EP (C-terminal fragment). Both doses of Org OD 14 induced a significant dose-related increase in plasma and pituitary lobe beta-EP concentrations as compared with the results on placebo treatment. By comparison, EB was active only at a dose of 10 micrograms/day. Despite the common stimulatory effects of EB and Org OD 14 on pituitary beta-EP, these findings suggest that the two steroids have different modes of action. The second part of the study investigated the changes in beta-EP and beta-lipotrophin (beta-LPH) plasma levels in a group of post-menopausal women treated for 6 months with Org OD 14 (2.5 mg/day) in comparison with the levels in a placebo-treated group. The clinical efficacy of Org OD 14 treatment in post-menopausal symptoms was confirmed, as well as its lack of or only transient effect on plasma lipids and lipoproteins. beta-EP and beta-LPH plasma levels were significantly higher in the Org OD 14-treated group than in the placebo group as from the second month until the end of the observation period.
 
Article
The results of a 2-year placebo-controlled study in 38 female patients with osteoporosis are presented. This study was conducted to evaluate the efficacy of a daily oral dose of 2.5 mg Org OD 14 ((7 alpha, 17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one) in the treatment of established osteoporosis. Org OD 14 is a steroid which shows combined weak oestrogenic, androgenic and progestational activity. A total of 31 patients completed a 12-month study period (17 placebo, 14 Org OD 14) and 25 of these went on to complete the full 24-months (15 placebo, 10 Org OD 14). A significant increase in bone mineral density as measured by dual photon absorptiometry was recorded in the lumbar spine in the Org OD 14-treated patients at 8, 16 and 24 months. The gain in bone mass after 8 months averaged 4% (P less than 0.01) and after 24 months 8% (P less than 0.001). In the control group, a bone loss rate of 2% per year was recorded in the lumbar spine. No significant changes in bone density in the forearm as assessed by single photon absorptiometry were found in either group. The increase in spinal bone density in the Org OD 14 group was non-linear and followed an S-shaped upward pattern. Org OD 14, while inducing no appreciable endometrial stimulation, was found to be a bone-active compound with anti-resorbing as well as anabolic activity. Org OD 14 warrants consideration not only for the long-term prevention of bone loss but also for curative treatment of post-menopausal osteoporosis.
 
Article
The effects of a new synthetic steroid Org OD 14 on the haemostatic mechanism were investigated in 60 post-menopausal women, randomly allocated to 12 weeks of treatment with either 2.5 mg/day of Org OD 14 or a placebo in a double-blind, group-comparative study. Assessments were made 2 weeks before and just prior to the start of treatment, at weeks 6 and 12 during treatment, and 2 weeks after its cessation. No significant differences between the two groups were found with regard to prothrombin time, kaolin cephalin clotting time (KCCT), clotting factors VII, VIII and X, white blood count (WBC) or transaminases (ASAT, ALAT). The following statistically significant differences were seen in the Org OD 14 group: higher plasminogen, antithrombin III, haemoglobin, haematocrit and platelet count, and increased fibrinolytic activity on fibrin plates, as well as lower fibrinogen and alkaline phosphatase values. These findings indicate that Org OD 14 displays no adverse effects on coagulation, while changes in fibrinolysis seem to be beneficial for post-menopausal women.
 
Article
The clinical profile of Org OD 14 ((7 alpha,17 alpha)-17-hydroxy-7-methyl-19-norpregn-5 (10)-en-20-yn-3-one) is remarkable in that the compound demonstrates simultaneous weak oestrogenic, androgenic and progestational activity after oral administration to animals. It was therefore studied to evaluate its efficacy in the treatment of the climacteric syndrome. Clinical data demonstrating these combined hormonal effects are reviewed in this paper: Administration of 2.5 mg/day Org OD 14 suppressed gonadotrophins in post-menopausal women and inhibited ovulation in fertile women. In post-menopausal women virtually no endometrial proliferation was induced, only occasional, very slight proliferation being seen. Even after 2 yr of therapy no endometrial hyperplasia was observed. A weak stimulatory effect on the vaginal mucosa was apparent. In addition, Org OD 14 prevented post-menopausal bone loss and alleviated vasomotor climacteric symptoms effectively. It also had a beneficial effect on mood and libido. Org OD 14 was well tolerated. The incidence of side effects (changes in body weight, vaginal bleeding) was low and similar to that with placebo treatment. Extensive safety studies of up to 5 yr duration, including liver function tests and metabolic studies, indicated no untoward effects. It was concluded that Org OD 14 is an effective and safe new preparation for the treatment of climacteric patients.
 
Article
A multicentre study covering 69 post-menopausal or oophorectomized women was performed to determine whether Org OD 14 [7 alpha, 17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one) administered orally in a daily dose of 2.5 mg for 90 consecutive days induces endometrial proliferation. The treatment with Org OD 14 was continued in combination with 1 mg/day of lynestrenol from day 91 for 10 days to ascertain whether secretory transformation of the endometrium and subsequent withdrawal bleeding would occur. Endometrial biopsies were obtained before treatment and on day 91. The effects of Org OD 14 on vaginal mucosa and cervical mucus were also evaluated. Org OD 14 did not display any effect on the endometrium in 56 of the study subjects (83.5%). Weak stimulation (initial proliferation) was seen in 11 of the subjects (16.4%) and withdrawal bleeding occurred in only 5 of these after cessation of the combined treatment with lynestrenol. However, moderate 'oestrogenic' effects on vaginal mucosa and cervical mucus were induced in all study subjects.
 
Article
Org OD 14 (7 alpha,17 alpha-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one) is a steroid possessing mixed hormonal activity, which in earlier studies has been shown to alleviate climacteric complaints and to prevent post-menopausal osteoporosis without affecting the endometrium. The effects of Org OD 14 on climacteric complaints were compared with those of oestradiol valerate (E2V) and placebo in a randomized, double-blind, cross-over study in 20 women who had been oophorectomized and hysterectomized 3-6 yr earlier as part of their treatment for cervical cancer. Each patient was treated orally for a total period of 18 wk, comprising 6 wk on each preparation. Capsules of identical appearance were given; these contained either 2.5 mg Org OD 14, 2 mg E2V or placebo. The patients' scores for symptoms and mood items on standardized rating scales were recorded at the end of each 6-wk treatment period (i.e. on days 43, 85 and 127). There were no differences between the effects of Org OD 14 and E2V on symptoms and mood items, while both compounds were more effective than placebo. Our findings confirmed that Org OD 14 is effective in ameliorating oestrogen deficiency symptoms in climacteric women.
 
Article
98 post-menopausal women were randomly allocated to either Org OD 14 [(7 alpha, 17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one] 2.5 mg/day or placebo. Treatment was continued for up to 6 yr. Any thromboembolic episode that occurred was recorded. Prothrombin time (PT), partial thromboplastin time (PTT), factor VII level and factor X level were measured prior to treatment and at yearly intervals. Antithrombin III level was measured in the last two yr of the study. There was one cerebrovascular accident after 3 months of placebo therapy but no other thromboembolic episodes. No significant difference was found between the effects of Org OD 14 and placebo with regard to any clotting factors at any time interval, although factor VII and factor X levels were consistently lower in the OD 14 group than in the placebo group. Antithrombin III levels measured after 5 and 6 yr were significantly higher (P less than 0.01) in the OD 14 group, suggesting a reduced risk of thrombosis in the treatment group.
 
Article
The effects of treating climacteric complaints in post-menopausal women were studied in an open trial in which Org OD 14, a placebo and no treatment were compared. In addition to the symptomatic effects, clinical and laboratory parameters were also studied. One hundred and twenty-four women who had undergone a natural or surgical menopause completed 4 mth of randomized treatment; 35 received Org OD 14 (2.5 mg/day, per os), 46 a placebo, and 43 no treatment. The mean ages and time in years since menopause were comparable for each group. The parameters were assessed before treatment and after 4 mth. The results in the group treated with Org OD 14 were compared statistically with those for the other two groups using the chi 2 test, Student's t test or analysis of variance. A beneficial effect on clinical parameters was seen following Org OD 14 treatment. The results as regards hot flushes and sweating were significantly better statistically than those in the other groups. Org OD 14 was found to have no effect on the endometrium, breasts, body weight or blood pressure, while vaginal atrophy was slightly improved. Serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and phosphate were slightly reduced by Org OD 14. Liver function tests, clotting factors and the other routine laboratory parameters were not affected by Org OD 14 treatment. It was concluded that Org OD 14 is an effective and safe compound for the treatment of climacteric syndrome.
 
Article
Long-term therapy with (7 alpha,17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (Org OD 14; tibolone, Livial) has no influence on the endometrium in post-menopausal women. This was concluded from endometrial biopsies taken from 39 post-menopausal women treated with 2.5 mg/day for periods of from 3 months to 5 years 11 months at three centres. These results accord with the data published so far on 129 women who have been treated for up to 2 years. A review of the data relating to a total of 168 patients treated with Org OD 14 is presented. The endometrial pattern observed at the start of therapy showed no change during treatment in 90% of patients. In 15 cases slight proliferation was apparent after treatment, this being a similar pattern to that seen in the initial days of a normal cycle. In a considerable number of patients no tissue could be obtained, indicating an atrophic pattern. The picture following Org OD 14 therapy was the same as that observed in untreated normal post-menopausal women.
 
Article
To describe the patient-reported impact of urinary incontinence (UI) in treatment-seeking women in Europe. PURE was a non-interventional, observational study, which aimed to describe the direct costs of treatment for European women seeking treatment for UI. A secondary study objective was to describe the impact of UI on health-related quality of life (HRQoL) by UI subtype and severity of disease. This paper presents the results from quality of life assessments as well as bothersomeness and interference with daily activities from the first study observation. Nine thousand four hundred and eighty-seven European women who had UI symptoms in the last 12 months were enrolled. Their UI symptoms were frequently those defined as mixed urinary incontinence (MUI) and were moderate to severe in nature. HRQoL was assessed at the first observation using the urinary Incontinence-specific Quality of Life Questionnaire (I-QOL) and the EQ-5D, a generic quality of life questionnaire. Data collected from EQ-5D provided insight into the patients' general health perception, while the I-QOL data indicated how affected the women were about their UI symptoms. Higher EQ-5D and I-QOL scores represent better quality of life. Patients were asked to indicate how much UI symptoms limited selected activities and to indicate the degree to which they found their symptoms to be bothersome. Overall, the median self-rated health status on the EQ-5D visual analogue scale (VAS) was 70.0 and the median EQ-5D health state index was 0.85, with small but noticeable differences observed between countries. Of the five health dimensions of the EQ-5D, patients' self-care appeared to be the least affected by UI, with fewer than 10% of the women reporting that they had some problems. Between 20 and 40% of patients had some problems with their mobility and usual activities, or had pain/discomfort or anxiety/depression. However, the impact of existing co-morbidity was not assessed and may have affected some women's scoring of the EQ-5D domains. The mean total I-QOL score overall was 57.7 and of the three subscales of the I-QOL, psychosocial impact had the highest overall scores, representing fewer problems, with lower scores observed for the avoidance and limiting behaviour subscale, and even lower scores for the social embarrassment subscale. The greatest patient-reported impact of UI symptoms on activities was on exercise, with more than 45% of patients moderately to totally limited in this activity. In most of the countries, more than 60% of the women reported that they were moderately to extremely bothered by their UI symptoms. There was considerable impact of UI on HRQoL in a treatment seeking population, as demonstrated by the disease-specific quality of life scale and by the high percentage of patients who were bothered by their symptoms.
 
Article
In a randomized, double-blind, placebo-controlled efficacy and safety study of Org OD 14 [(7 alpha,17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one] in 60 post-menopausal women, the effects of treatment on clinical parameters (hot flushes and associated complaints) and laboratory parameters (routine haematology and biochemistry) were evaluated. Assessments were made before treatment and after 1, 3, 6, 9 and 12 mth of therapy (in the case of the laboratory parameters after 6 and 12 mth only). In total, 17 patients dropped out, 6 of whom were on Org OD 14 and 11 on placebo. Clinical parameters were evaluated by means of the Yates test. Org OD 14 had a significantly better effect than placebo on hot flushes and sweating at all stages of assessment. A similar effect, albeit to a lesser extent, was seen on sleeplessness, fatigability, irritability and psychic instability. Serum levels of alkaline phosphatase, triglycerides, high-density lipoprotein cholesterol and phosphate decreased during Org OD 14 treatment. It was concluded that Org OD 14 provides a new, efficient and safe means of treating the post-menopausal syndrome.
 
Article
A novel steroid, (7 alpha,17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-yn-3-one (code name Org OD 14), was found to possess concomitant weak oestrogenic, androgenic and progestational activities. The effects observed in other tests, viz. inhibition of ovulation in rats, prevention of bone loss following ovariectomy in rats and restoration of sex drive in castrated male rats, corresponded to this hormonal profile. Studies of the metabolites of Org OD 14 in rats suggested that these are involved in the complex endocrinological properties displayed by the compound.
 
Article
Org OD 14 is a synthetic steroid which in animal bioassays displays oestrogenic as well as very weak androgenic-anabolic properties. Earlier studies have shown that it alleviates oestrogen-deficiency symptoms and retards osteoporosis. OD 14 can be administered continuously with little effect on the endometrium. The aim of this study was to evaluate the effect of OD 14 on apolipoprotein A1 (Apo-A1), the major protein constituent of the high-density lipoprotein (HDL) fraction, as compared with that of oestradiol valerate (E2V) and a placebo. Twenty-two women, who had been oophorectomized when undergoing surgical treatment for stage IB or IIA cervical carcinoma, were given OD 14 2.5 mg/day, a placebo, and E2V 2 mg/day for a period of 6 wk in each case using a double-blind, cross-over method. Serum Apo-A1 was determined by electro-immunoassay after each treatment period. There was a marked decrease in Apo-A1 after OD 14 as compared with the levels seen after the placebo and E2V. This decrease is interpreted as evidence of a strong androgenic influence by OD 14. In epidemiological studies low levels of Apo-A1 have been associated with a higher incidence of atherosclerosis and cardiovascular disease. Long-term treatment with OD 14 might therefore be hazardous in this respect.
 
Article
The effects of 2.5 mg/day 7 alpha, 17 alpha-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (Org OD 14) on lipid metabolism, with particular reference to high-density lipoprotein (HDL)-related variables, were assessed in 14 healthy post-menopausal women after 12 and 36 mth of treatment. There were significant reductions in the following variables after both treatment periods: total phospholipids, total triglycerides, HDL-phospholipids and apolipoprotein A1. No changes were observed in total cholesterol or low-density lipoprotein (LDL) cholesterol over the entire treatment period. A significant but temporary decrease was observed in HDL-cholesterol after 12 mth, with a return to pretreatment values after 36 mth of treatment. The findings of this study clearly show that Org OD 14 has no adverse effects on the atherogenic variables, viz. LDL-cholesterol and triglycerides. Indeed, since the latter were lowered, its action is in fact beneficial. Moreover, its effect on HDL-cholesterol, the anti-atherogenic variable, is only temporary. We concluded from this study that although the composition of HDL changes during Org OD 14 treatment (especially as regards its cholesterol content), there is no evidence that reverse cholesterol transport is impaired.
 
Article
Using a 24-h whole-body retention (WBR) of Tc99m hydroxyethylidene diphosphonate (HEDP), a sensitive measure of skeletal metabolism, 24 women receiving the synthetic steroid hormone Org OD 14 were studied. OD 14 was found to have a powerful suppressive effect on skeletal metabolism in both oophorectomized and non-oophorectomized women when compared with control subjects (P less than 0.001 and P less than 0.01, respectively). The degree of suppression was similar to that found with oestrogen therapy. While it has previously been shown that OD 14 prevents bone mineral loss (as measured by photon-absorptiometry), the present study provides further evidence as to the efficacy of this compound in suppressing skeletal metabolism.
 
Article
The cardiovascular effects of Org OD 14, a synthetic steroid which relieves climacteric symptoms without stimulating the endometrium, were assessed in a group of healthy post-menopausal women. Limb blood flow was measured by venous occlusion plethysmography. Resting forearm blood flow, the dilator response to anoxic exercise and heart rate increased significantly after six weeks of drug treatment. Hand flow was unchanged. The cardiovascular effects of Org OD 14 differ from those seen with oestrogens, in keeping with the unique pharmacological profile of this steroid.
 
Article
Hormonal profiles were studied in 15 post-menopausal women, 7 of whom had been treated with Organon OD 14 (Tibolone) and 8 with placebo tablets for 3 yr. In the Tibolone-treated group, the sex hormone binding globulin (SHBG) levels were significantly lower, while the estimated free testosterone levels, the testosterone/SHBG ratio and the thyroid-stimulating hormone (TSH) response to thyrotrophin-releasing hormone (TRH) were significantly higher than in the placebo group. Prolactin and triiodothyronine (T3) concentrations were lower in the actively treated group, although the differences were not statistically significant. No significant differences were observed with respect to thyroxine (T4), TSH, basal cortisol or cortisol response to synacthen.
 
Article
In view of the increasing use of oestrogen-progestogen therapy in post-menopausal women the availability of possible biochemical marker of endometrial response to progestogen would be highly desirable. Placental protein 14 (PP14) has recently been shown to be excreted from the endometrium during the secretory phase of the menstrual cycle. In the present study we examined the concentration of serum PP14 (S-PP14) in 15 pre-menopausal women during the menstrual cycle and in 30 early post-menopausal women receiving three different doses of 17 beta-oestradiol (E2), cyclically combined with norethisterone acetate (NETA). S-PP14 levels peaked on day 1 following the onset of menstrual bleeding and on day 7 during NETA administration. It was possible to estimate the area under the S-PP14 curve reliably from one or two blood samples taken at optimal times. In the post-menopausal women, S-PP14 varied in a highly significant dose-dependent manner, i.e., the higher the E2 dose (in relation to the fixed NETA dose) the higher the S-PP14 response was found to be. We suggest that S-PP14 measurements might reflect the quantitative development of the endometrium in the secretory phase in both pre-menopausal and post-menopausal women.
 
Article
To describe the characteristics of women seeking treatment for symptoms of urinary incontinence (UI) in European countries. Prospective urinary incontinence research (PURE) was a 6-month, observational, pan-European study, primarily aimed at determining the direct costs of urinary incontinence treatment. The secondary objectives of PURE were to describe the impact of UI on health-related quality of life (HRQoL) in treatment seeking patients and to illustrate the treatment patterns for UI in Europe. One thousand and Fifty-five physicians from 14 European countries, including general practitioners (GPs), gynaecologists, urologists and geriatricians, observed women seeking treatment for their UI and recorded data at the first observation and then prospectively at 3 and 6 months after the first observation during the normal course of therapy. Women of at least 18 years of age who had experienced urinary leakage in the 12 months prior to enrolment in the study, who were seeking treatment or under treatment for UI and who presented within the normal course of UI care were included in the 6 months study. The first observation characteristics of the patients are described here. Demographic characteristics, as well as disease and treatment status at first observation were explored using descriptive summary statistics to gain an understanding of the population studied. In total, 9487 women took part in PURE, with the largest patient groups from Germany, Spain and the UK/Ireland. The majority of women were post-menopausal and had a mean age of 60.7 years, were not current smokers and tended to be overweight (BMI > 25.0). Overall, mixed UI symptoms were more common than SUI and UUI, as defined by clinical opinion (SUI 38%, MUI 42% and UUI 18%), and by a two-item questionnaire, the S/UIQ (SUI 29%, MUI 58% and UUI 13%). Around half of the patients (48%) suffered from their symptoms for less than 2 years before consulting a physician; 28% delayed seeking treatment for 3-5 years, with 13% waiting for 6-10 years and the remaining 11% waiting for 11 or more years. Some of the described patients' characteristics may provide important information to clinicians to enable them to take a more active approach to case-finding, which will ultimately benefit the incontinent patient.
 
Article
Hot flushes are experienced in those periods of the female life when estrogen levels are low. Hormone replacement therapy is thus the first choice for treatment of hot flushes. However this treatment is not always accepted or contraindicated for a variety of reasons. Estrogen (and progestogen) strongly interact with a number of neurotransmitters and this has led to a range of non-hormonal treatments including compounds that act via the noradrenergic or dopaminergic systems as well as herbal remedies. These treatments (which are shortly reviewed) are not always successful. Surprisingly, apart from treatment with some selective serotonin (5-HT) reuptake inhibitors (SSRI's), up till now, little attention is given to the strong interaction of estrogens with the serotonergic system. These interactions are shortly reviewed. Based on these interactions, a hypothesis on the genesis of hot flushes is postulated. Especially the 5-HT(2A) receptor subtype may play a key role in the occurrence of hot flushes. A number of arguments that support this hypothesis are discussed.
 
Article
The aim of the present study was to ascertain the cumulative incidence of first hormone replacement therapy (HRT) and the factors that predict its prescription. In a general population 1689 women were followed for 9 months in order to trace first HRT prescriptions. Determinants (well-being, attitude towards menopause, menopausal status and another 9 variables) were measured by means of a questionnaire. Data analyses were performed for all women and for women with or without typical climacteric complaints. The cumulative 9 month incidence of HRT was 6.2%. For women without typical complaints a lower level of well-being (odds ratio 5.5; 95% CI 1.9-15.5) and the former use of the contraceptive pill (odds ratio 4.6%; 95% CI 1.0-20.5) were independently associated with HRT prescription. For women with typical complaints a positive attitude towards 'menopause should be treated' (odds ratio 3.8; 95% CI 1.8-8.0) was a determinant of HRT prescription. The cumulative incidence of HRT prescription is high, but from additional data it is apparent that within a period of 1 year and 9 months the majority of women stop taking HRT. For women without typical complaints, physicians prescribe HRT five times more often to those with a lower level of well-being. For women with typical complaints the physician's prescription is primarily related to the woman's attitude towards (medical) treatment of the menopause.
 
Article
To evaluate low doses of 17 beta-estradiol (E2) and norethisterone acetate (NETA) as continuous combined hormone replacement therapy (HRT) in their effects on vasomotor symptoms, bleeding episodes, endometrial histology and mastalgia. Sixty postmenopausal women were randomly allocated to three treatment groups and were given 1 mg E2 and 0.25 mg NETA (A), 1 mg E2 and 0.5 mg NETA (B) and 2 mg E2 and 1.0 mg NETA (C) in daily doses. The treatment period was 1 year. A similar statistically significant reduction of climacteric symptoms (P < 0.05) was found in all groups. Bleedings, mainly as spottings, occurred most commonly during the first treatment months. Fewer bleeding episodes and a higher percentage of amenorrhea was noted in group B compared to the other groups but did not reach statistical significance. All endometrial biopsies showed atrophy. Women in group A and B had less severe mastalgia (P < 0.05) compared to group C, given higher doses of steroids. Postmenopausal women taking 1 mg of E2 plus 0.5 mg NETA as continuous combined HRT reported a marked reduction of climacteric complaints and good bleeding control. No endometrial proliferation was detected after 1 year of treatment. This type of therapy may be beneficial especially for elderly women, in whom bleeding may be annoying.
 
Article
To assess the effects of Femoston (2 mg micronised 17 beta oestradiol daily, sequentially combined in one tablet with 10 mg dydrogesterone for 14 days per 28 day cycle) on the serum lipid profile of postmenopausal women. 188 healthy postmenopausal women with intact uteri (aged 40 to 65 years) were enrolled in an open, multicentre, one-year study. Serum lipids and lipoproteins were measured at baseline and after 3, 6 and 12 months. A total of 155 women completed the one-year study. Mean serum levels of total cholesterol and low-density lipoprotein (LDL)-cholesterol were significantly reduced (P < 0.01) at all assessments compared with baseline; the reductions observed at the final assessment were 5 and 20%, respectively. A significant increase of 20% (P < 0.01) was seen in high-density lipoprotein (HDL)-cholesterol levels by month 12. Mean levels of triglycerides were also increased (p < 0.01). Blood pressure and heart rate remained unchanged throughout the study. The results show that the overall effects of Femoston on the serum lipid profile are comparable to those found with oestrogen therapy alone and should reduce the risk of cardiovascular disease in postmenopausal women.
 
Article
To compare the effectiveness of tibolone and 17beta-estradiol on climacteric symptoms, in a randomized, single-blind, cross-over study in surgically menopausal women. Forty surgically menopausal women were divided randomly into two groups. Group A received treatment with tibolone for 6 months, while group B received 17beta-estradiol. After 3 weeks washout period, treatment protocols were exchanged for another 6 months. The climacteric symptoms were assessed with Greene Climacteric Scale at baseline, during washout and after the treatments. Statistical analysis was done with the Wilcoxon's Sign Rank test. Both treatments significantly improved the scores of all subscales with respect to baseline. However, the improvement in psychological, somatic and sexual subscales were significantly superior in the tibolone group compared with 17beta-estradiol group. Both treatments showed comparable improvements in the relief of vasomotor symptoms. Our findings suggest that tibolone may improve mood, libido and somatic symptoms in surgically menopausal women to a greater extent than estrogen therapy alone.
 
Article
The plasma protein distribution of oestradiol (E2) and oestrone (E1) during transdermal E2 administration (100 micrograms/24 hr) was studied in 12 post-menopausal women. The E2 and E1 levels observed were 43-83 pg/ml and 37-73 pg/ml, respectively. The levels of the free, albumin-bound and sex-hormone-binding globulin (SHBG) bound fractions were in the ranges 1.4-1.9%, 60-65% and 35-45%, respectively, in the case of E2, and 2.8-3.0%, 80-89% and 15-20%, respectively, in that of E1. The SHBG levels also remained unaltered. It was concluded that transdermal administration of E2 at the dosage employed produces a physiological plasma protein distribution of E2 and E1 and does not affect liver protein production.
 
Top-cited authors
Andrea Riccardo Genazzani
  • Università di Pisa
Camil Castelo-Branco
  • University of Barcelona
Marco Gambacciani
  • Università di Pisa
Mats Hammar
  • Linköping University
Huber Johannes