Effects of tibolone on body composition in postmenopausal women: a 1-year follow up study

Objective: We investigated the effects of 1-year tibolone treatment on body weight, body composition and indices of android obesity in postmenopausal women.

Methods: Forty-four postmenopausal women participated in this open-label controlled study; mean age was 51.8 ± 2.21 years and all women were menopausal for 3.8 ± 1.40 years. Twenty-two of them started taking 2.5 mg tibolone (TIB) daily for 1 year, whereas the remaining 22 served as age-matched controls. All subjects underwent a structured interview, physical examination, body composition measurements performed by dual-energy X-ray absorptiometry (DXA) — Hologic QDR 4500 A, as well as bioelectrical body impedance analysis (BI) — Tanita TBF-215, Japan.

Results: The TIB group did not significantly increase their weight (+0.4 kg), while the non-treated controls increased their mean weight by 1.4 kg (p = 0.046). In the TIB group, DXA showed a non-significant body fat decrease by a mean of 0.5 kg and a non-significant lean mass increase by 0.8 kg, while in the control group, fat mass increased by 1.7 kg (p = 0.032) and lean mass did not change. BI revealed that the TIB group had lost some fat (≈0.6 kg, n.s.) and put some free-fat mass (≈1.0 kg, p = 0.048) without changes in total body water. The control group put on some fat (≈1.1 kg, p = 0.042) and lost some body water (≈0.4 kg, n.s.).

Conclusion: Results from both methods of measuring body composition show a similar trend: a decrease in fat mass and an increase in lean mass in TIB treated subjects. From the body composition perspective, tibolone may be regarded as a preferential alternative to conventional hormonal therapy (HT) in postmenopausal women.     

Endometrial cancer patients and tibolone: a matched case-control study

OBJECTIVE: To evaluate whether tibolone had adverse effects on the prognosis of endometrial cancer patients. METHODS: In this retrospective matched case-control study, out of 396 patients with endometrial cancer from January 1997 to December 2002, 68 patients who underwent complete surgical staging were identified as tibolone users (cases). For each case, one control as tibolone non-user was matched for stage and grade of disease, in this order of priority (ratio users: non-users, 1:1). RESULTS: There were no significant differences in age (p = 0.11), stage (p = 1.00), grade (p = 0.96) and treatment modality (p = 0.55) between two arms. The mean duration of follow-up for tibolone users and tibolone non-users is 48.0 months and 54.4 months, respectively (p = 0.12). In tibolone users, a total of four patients recurred and two out of four patients died of disease. In tibolone non-users, there were three recurrences and all of three patients died of disease. There were no significant differences in disease free survival (p = 0.52) and overall survival (p = 0.61) between two arms. And there was no significant difference in disease free survival according to the duration of tibolone use (p = 0.14). CONCLUSION: There was no evidence that tibolone had adverse effects on the disease free survival and overall survival of endometrial cancer patients. So, tibolone could be used in these patients.     

Comparison of the effects of tibolone and estrogen replacement therapy on echocardiographic basic cardiac functions in post-menopausal women: a randomized placebo controlled study

Objectives: This study is designed to investigate and compare the effects of synthetic steroid tibolone and HRT on systolic and diastolic heart functions in post-menopausal women. Methods: This prospective, randomized placebo controlled double blind study was conducted in a university clinic. Fifty-eight non-smoking, otherwise healthy post-menopausal women who did not receive any kind of HRT at least for 3 years within the onset of menopause were included in the study. The patients were randomly allocated to either 2.5 mg per day tibolone (OD, n=18), daily combined 0.625 mg of conjugated estrogens 2.5 mg⁻¹ of medroxy progesterone acetate pill (EP, n=20) or a vitamin pill (n=20) in a double blinded fashion. Their basic systolic and diastolic functions were investigated with HP Sonos-1000 echocardiography using standard positions and windows before and 6 months after the initiation of HRT. Results: Mean age, weight, length of post-menopausal period, heart rate, systolic and diastolic pressures were similar between the groups. At the initiation of the study all groups had similar echocardiographic measurements. However, at the end of 6 months, left ventricular end-systolic and -diastolic volumes were decreased significantly compared to pretreatment and placebo in both EP and OD treated groups. (55.5±18.4 and 53.7±19.1.8 ml; 109.9±19.9 and 110.7±20.8 ml versus 74.5±14.9 and 142.7±19.1 ml, respectively; P<0.05). Improvement in diastolic functions was significant in EP/OD groups compared to pre-treatment period and the placebo groups (E/A 1.34±0.1 and 1.38±0.1 versus 1.18±0.09, deceleration time 204±11.1 and 202.8±27.1 ms versus 237.6±26.9 ms, respectively). Besides increase in left ventricular mass adjusted for height, decrease in left ventricular relative wall thickness, and systemic vascular resistance were significant in EP and OD treated groups than placebo and the pre-treatment measurements. Although improved in both OD and EP groups, the changes in systolic and diastolic functions were significantly higher in the OD treated group. Based on our preliminary results, we may conclude that both EP and OD regimens may improve cardiac performance and age related dysfunctions. Conclusion: The present results may further support that both OD and EP exert many direct effects on cardiovascular system other than metabolic changes regarding lipoproteins. The greater improvement in the OD group may be explained by its weak androgenic activity which is consistent with the in vitro data that androgens are potent relaxing agents on coronary arteries and restores cardiac myosin isoenzyme and ATPase patterns which mandates further clinical studies.     

Effects of tibolone and combined 17beta-estradiol and norethisterone acetate on serum C-reactive protein in healthy post-menopausal women: a randomized trial

BACKGROUND: Serum C-reactive protein (CRP) is an independent risk factor for the development of cardiovascular diseases in healthy post-menopausal women. Oral unopposed and progestin-combined 17beta-estradiol (E(2)) increase serum CRP in post-menopausal women. The aim of this study was to compare the effects of tibolone, a steroid with estrogenic, androgenic or progestogenic properties, with a combination of E(2) and norethisterone acetate (E(2) + NETA) on serum CRP levels in healthy post-menopausal women. METHODS: A total of 139 post-menopausal women (mean age: 55 years, range 44-48) was randomly assigned to receive tibolone 1.25 mg/day (n = 52), tibolone 2.5 mg/day (n = 39) or E(2) 2 mg/day plus NETA 1 mg/day (n = 48) for 2 years. Serum CRP was measured at baseline and at 6, 12 and 24 months. RESULTS: Both doses of tibolone and E(2) + NETA increased serum CRP by a similar extent as soon as 6 months with a sustained effect over the 24 month treatment period. For example, after 6 months of treatment, serum CRP increased by a median of +106% (P < 0.001), +89% (P < 0.05) and +139% (P < 0.001) for tibolone 1.25 mg/day, tibolone 2.5 mg/day and E(2) + NETA respectively. CONCLUSIONS: Tibolone and E(2) + NETA significantly increase serum CRP levels in healthy post-menopausal women to a comparable extent. Relationships between induced elevated CRP levels with tibolone and E(2) + NETA and cardiovascular events require further studies.     

The effect of tibolone versus 17beta-estradiol on climacteric symptoms in women with surgical menopause: a randomized, cross-over study

OBJECTIVE: To compare the effectiveness of tibolone and 17beta-estradiol on climacteric symptoms, in a randomized, single-blind, cross-over study in surgically menopausal women. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSION: Our findings suggest that tibolone may improve mood, libido and somatic symptoms in surgically menopausal women to a greater extent than estrogen therapy alone.     

Pentoxifylline versus placebo in the treatment of infertility associated with minimal or mild endometriosis: a pilot randomized clinical trial

The present study is the first prospective randomized controlled trial of the effect of pentoxifylline on future fertility in infertile women with asymptomatic minimal or mild endometriosis. After completion of a basic infertility workup and laparoscopy, patients were entered into the study and randomly allocated to receive either a 12 month course of oral pentoxifylline (800 mg/day) (n = 30) or an oral placebo (n = 30). Those patients with other infertility factors were included in the study only if the factors were correctable and ultimately determined to be non-contributory. Life-table analysis was used to compare pregnancy rates between the two groups over a 12 month period that started immediately after laparoscopy. The 12 month actuarial overall pregnancy rates were 31 and 18.5% in the pentoxifylline and placebo groups respectively. However, this difference was not statistically significant by the chi(2)-test. Similarly, the Cox regression method showed no differences between the hazard of pregnancy in the two groups studied (odds ratio, 0.56; 95% confidence interval, 0.18-1.67). Therefore, there is no evidence from this study that immunomodulation with pentoxifylline aids fertility in those women with minimal or mild endometriosis. Further studies including more infertile patients with endometriosis are desirable in order to confirm our results.      

Mammographic changes associated with raloxifene and tibolone therapy in postmenopausal women: a prospective study

OBJECTIVE: The prolonged use of estrogen therapy is associated with a slightly increased risk of breast cancer. Alternative therapies that are effective in the prevention of menopause, having associated morbidities but no unwanted effects, are of primary interest in the pharmacologic research. The aim of this study was to evaluate the effect of two alternative to estrogens drugs, the selective estrogen receptor modulator raloxifene and the tissue-specific tibolone, on the mammographic appearance of the breast. DESIGN: The study group comprised 131 postmenopausal women aged 41 to 67 years. The women were at least 2 years postmenopausal, free of climacteric symptoms, and at the time of entry to the study had not had therapy for at least 9 months. Women with risk factors for osteoporosis or cardiovascular disease were allocated either to tibolone (n = 56) or raloxifene (n = 48) therapy. Women with no risk factors and women who either did not qualify for or denied treatment (n = 27) served as controls. The study duration was 12 months. Women received a baseline mammogram before commencing therapy and a repeat mammogram at the end of the study period. Mammogram findings were classified according to the modified Wolfe criteria by two expert radiologists. RESULTS: No difference was identified between groups with respect to baseline characteristics associated with breast cancer risk. Similarly, no difference was detected between groups concerning the modified Wolfe classification of baseline mammographic findings. In the tibolone group, 10.7% of the women showed an increase in breast density in the 12-month reevaluation. The respective figure in the raloxifene group was 6.3%, whereas no woman in the control group showed an increase in breast density. Differences in the increase in breast density between groups did not, however, reach statistical significance. Accordingly, 10.7% of women in the tibolone group and 18.8% of women in the raloxifene group exhibited involutionary changes in the repeat mammogram, whereas 25.9% of women in the control group revealed a decrease in breast density in the 12-month examination. The percentages were not significantly different between groups. CONCLUSIONS: Breast density as shown by mammography was stable in a majority of patients and changed in a minority of cases for both tibolone and raloxifene. In most patients, these drugs are not likely to interfere with mammogram interpretation. Larger long-term studies are needed to confirm the impact of prolonged tibolone or raloxifene administration on mammography.     

Postmenopause hormone treatment in women with NIDDM or impaired glucose tolerance: the MEDIA randomized clinical trial

OBJECTIVE: To assess the biological safety of four hormone replacement treatment (HRT) combinations in women with non insulin dependent diabetes mellitus (NIDDM) or impaired glucose tolerance (IGT). SUBJECTS AND METHODS: Randomized, double-blind, placebo-controlled trial to analyze the variation of fibrinogen, factor VII, PAI1, and TG blood levels in women (n=99), with NIDDM or IGT, receiving a 3-month course of either oral oestradiol (1 or 2 mg) combined with Chlormadinone Acetate 5 mg, or transdermal oestradiol 50 microg/24 h in association with Norethisterone Acetate (11.2 or 22.4 mg), or placebo. Follow-up lasted 3 months. RESULTS: Ninety nine patients, mean age 56 years (SD 5), mean diabetes duration 7 years (S.D. 7), mean glycated hemoglobin (7.3%) were enrolled. There was no significant difference between the groups for any of the primary hemostasis criteria (n=77). Triglycerides (TG) variation significantly differed between groups, P=0.01, from -21% in the large patch group, to +22% in the placebo group (n=82). Treatment administration routes did not significantly differ for any of the criteria. There was a significant difference in the total cholesterol variation between groups, from +8.7% in the placebo group to -10.8% in the oral 1 mg group (P=0.001). CONCLUSION: The treatments had no highly deleterious effect in these patients with NIDDM or with IGT. Long-term trials can be performed with such patients, and an hormone treatment can be prescribed to relieve symptoms. Since these patients had a well-controlled NIDDM, results might be different in less well-controlled diabetes. The data do not support the hypothesis of an impaired oestrogen effect in patients with NIDDM.     

Testosterone aromatization and cognition in women: a randomized, placebo-controlled trial

OBJECTIVE: To explore whether inhibition of the conversion of testosterone to estradiol modifies the effects of testosterone on cognition in 61 healthy, estrogen-treated postmenopausal women. DESIGN: Seventy-six postmenopausal women using transdermal estrogen for at least 8 weeks, with a serum total testosterone less than 1.2 nmol/L participated in a single-center, double-blind, randomized, placebo-controlled study. All participants received transdermal testosterone, 400 muL of a 0.5% testosterone gel, daily and were randomized to receive either letrozole 2.5 mg/day or an identical placebo tablet. The main outcome measure was cognition, evaluated using a comprehensive battery of standardized neuropsychological tests, at baseline and week 16. RESULTS: Thirty women in each group completed the study. Free testosterone increased from baseline in both groups, with no difference between groups. Free testosterone levels achieved were below the 90th centile for young women in 80% of the participants at week 16. Serum estradiol and sex hormone-binding globulin levels did not differ from baseline or between groups during the study. No clinically significant effects of testosterone treatment were seen for attention and working memory, psychomotor speed, or executive function. Significant improvements were seen for immediate and delayed visual and verbal memory and for simple concentration with testosterone therapy, all of which were unaffected by the aromatase inhibitor. CONCLUSIONS: We did not observe any effects of aromatase inhibition on cognition in healthy, estrogen-treated postmenopausal women treated with testosterone. This may be due to insufficient study power or a true lack of effect. However, our findings highlight that the detection of subtle changes in cognition in well women require the development of sensitive instruments and large randomized, controlled trials.     

Candidaemia in a European Paediatric University Hospital: a 10-year observational study

In this retrospective observational study covering 1998 to 2008, 32 patients (mean age: 7.50 years) were identified that had 35 episodes of candidaemia (0.47 cases/1000 hospital discharges). Cancer/allogeneic haematopoietic stem cell transplantation (43%) and congenital malformations/syndromes (21%) were the predominant underlying conditions. Central venous catheterization (90%), a history of antibacterial therapy (69%) and previous bacteraemia (54%) were frequent comorbidities. Candida albicans (46%) was most common, followed by Candida parapsilosis (17%) and Candida glabrata (14%). Resistance was infrequent and limited to non-albicans Candida spp. The 30-day and 100-day mortality rates were 11.4%.     

Micronutrient supplementation increases genital tract shedding of HIV-1 in women: results of a randomized trial

To test the hypothesis that micronutrient supplementation decreases genital HIV-1 shedding, a double-blind, randomized, placebo-controlled trial of 6 weeks of multivitamin plus selenium supplementation vs. placebo was conducted among 400 HIV-1-seropositive, nonpregnant, antiretroviral-naive women in Mombasa, Kenya. Primary outcome measures included cervical and vaginal shedding of HIV-1-infected cells and RNA. Secondary outcomes included plasma viral load and CD4 count. Surprisingly, the odds of detection of vaginal HIV-1-infected cells were 2.5-fold higher (P = 0.001) and the quantity of HIV-1 RNA in vaginal secretions was 0.37 log10 copies/swab higher (P = 0.004) among women who received micronutrients in comparison to placebo, even after adjustment for potential confounders including baseline HIV-1 shedding and CD4 count. The increase in vaginal HIV-1 shedding was greatest among women who had normal baseline selenium levels. Micronutrient supplementation resulted in higher CD4 (+23 cells/microL, P = 0.03) and CD8 (+74 cells/microL, P = 0.005) counts compared with placebo but did not alter the plasma viral load. In this randomized trial, micronutrients resulted in higher levels of genital HIV-1 shedding compared with placebo. The potential benefit of micronutrient supplementation in HIV-1-seropositive women should be considered in relation to the potential for increased infectivity.     

Effect of decision aid for breast cancer prevention on decisional conflict in women with a BRCA1 or BRCA2 mutation: a multisite,randomized, controlled trial

PurposeWomen with a BRCA1 or BRCA2 mutation are at high risk for breast cancer and must make important decisions about breast cancer prevention and screening. In the current study, we report a multisite, randomized, controlled trial evaluating the effectiveness of a decision aid for breast cancer prevention in women with a BRCA mutation with no previous diagnosis of cancer.MethodsWithin 1 month of receiving a positive BRCA result, women were randomized to receive either usual care (control group) or decision aid (intervention group). Participants were followed at 3, 6, and 12 months; were asked about preventive measures; and completed standardized questionnaires assessing decision making and psychosocial functioning.ResultsOne hundred fifty women were randomized. Mean cancer-related distress scores were significantly lower in the intervention group compared with the control group at 6 months (P = 0.01) and at 12 months postrandomization (P = 0.05). Decisional conflict scores declined over time for both groups and at no time were there statistical differences between the two groups.ConclusionThe decision aid for breast cancer prevention in women with a BRCA1 or BRCA2 mutation is effective in significantly decreasing cancer-related distress within the year following receipt of positive genetic test results.Genet Med 19 3, 330–336.     

Quality of life assessment of treatment with dental appliance or UPPP in patients with mild to moderate obstructive sleep apnoea. A prospective randomized 1-year follow-up study

The objectives of this study were: to evaluate the change in the three quality of life (QOL) dimensions of vitality, contentment and sleep before intervention and 1 year after treatment with a dental appliance or uvulopalatopharyngoplasty (UPPP); to compare the effect of treatment between these two treatment groups on these three dimensions; and to determine the relation between the QOL scores and somnographic values. Ninety-five patients with mild to moderate obstructive sleep apnoea (OSA) (AI > 5) were randomly allocated to either a dental appliance or UPPP treatment group. Seven patients withdrew after randomization but before treatment, leaving 88 patients eligible for treatment. The patients were examined using somnography and administered the Minor Symptoms Evaluation-Profile (MSE-P), a QOL questionnaire, before and 1 year after intervention. Thirty-seven patients in the dental appliance group and 43 in the UPPP group completed the 1-year follow-up. The mean values for the three dimensions vitality, contentment and sleep improved significantly 1 year after intervention in the dental appliance and UPPP groups. No difference in the QOL scores at baseline was noted between the groups. One year after intervention the UPPP group showed significantly more contentment than the dental appliance group. In contrast, vitality and sleep dimensions did not differ between the two treatment groups. No significant correlations were observed between the QOL scores and somnographic values. In conclusion, quality of life improved significantly in the dental appliance and UPPP groups 1 year after intervention. However, the dental appliance group showed a lower level of contentment than the UPPP group, even though the somnographic values were superior in the former group.     

Raloxifene reduces procarboxypeptidase U, an antifibrinolytic marker. A 2-year randomized, placebo-controlled study in healthy early postmenopausal women

OBJECTIVE: The aim of this study was to compare the long-term effects of two dosages of raloxifene with oral hormone therapy (HT; conjugated equine estrogens combined with medroxyprogesterone acetate) on procarboxypeptidase U. DESIGN: In a randomized, double-blind, placebo-controlled, 2-year study, 95 healthy, nonhysterectomized, early postmenopausal women received either daily raloxifene 60 mg (n = 24), raloxifene 150 mg (n = 23), HT (conjugated equine estrogens 0.625 mg + medroxyprogesterone acetate 2.5 mg, n = 24), or placebo (n = 24). At baseline and after 6, 12, and 24 months, fasting plasma procarboxypeptidase U concentrations were measured. RESULTS: Six months of treatment with raloxifene 60 mg and raloxifene 150 mg were associated with significant decreases in plasma procarboxypeptidase U concentrations, which were sustained after 12 and 24 months. Raloxifene 60 mg: t = 0, 619 +/- 89 U/L (mean +/- SD); t = 6, 574 +/- 87 U/L; t = 12, 571 +/- 96 U/L; t = 24, 568 +/- 92 U/L; ANCOVA versus placebo, P = 0.026. Raloxifene 150 mg: t = 0, 608 +/- 67 U/L; t = 6, 580 +/- 73 U/L; t = 12, 578 +/- 70 U/L; t = 24, 562 +/- 61 U/L; ANCOVA versus placebo, P = 0.039. No significant changes were found in the HT group. CONCLUSION: Long-term treatment with raloxifene reduced procarboxypeptidase U plasma concentrations.     

Estrogen replacement therapy and cognitive functions in healthy postmenopausal women: a randomized trial

This study aimed to evaluate the effect of estrogen replacement therapy on verbal cognitive performance of middle-aged postmenopausal women. Middle-aged (40 to 59 years) hysterectomized, oligosymptomatic women receiving 0.625 mg/day of conjugated equine estrogens (N = 27) or placebo (N = 32) in a double-blind parallel group design were compared according to their performance on a verbal memory battery before and after six 28-day cycles of treatment. Both groups had similar age and educational level. The estrogen group performed better on digit span-forward and on the recall of the easy stimuli on the verbal-paired associates test regardless of age, education, physical symptoms, number of years of menopause, or blood estradiol levels. However, the small magnitude of difference in the effect on attentional span suggests that the estrogen-related improvement is unlikely to be of clinical relevance. Estrogen replacement therapy did not improve verbal memory in middle-aged, hysterectomized, postmenopausal, asymptomatic women.     

Multidimensional treatment foster care for girls in the juvenile justice system: 2-year follow-up of a randomized clinical trial

This study is a 2-year follow-up of girls with serious and chronic delinquency who were enrolled in a randomized clinical trial conducted from 1997 to 2002 comparing multidimensional treatment foster care (MTFC) and group care (N = 81). Girls were referred by juvenile court judges and had an average of over 11 criminal referrals when they entered the study. A latent variable analysis of covariance model controlling for initial status demonstrated maintenance of effects for MTFC in preventing delinquency at the 2-year assessment, as measured by days in locked settings, number of criminal referrals, and self-reported delinquency. A latent variable growth model focusing on variance in individual trajectories across the course of the study also demonstrated the efficacy of MTFC. Older girls exhibited less delinquency over time relative to younger girls in both conditions. Implications for gender-sensitive programming for youths referred from juvenile justice are discussed.