Santiago Palacios

Long-term treatment of uterine fibroids with ulipristal acetate ☆

OBJECTIVE To investigate the efficacy and safety of ulipristal acetate (UPA) for long-term treatment of symptomatic uterine fibroids. DESIGN Repeated intermittent open-label UPA courses, each followed by randomized double-blind norethisterone acetate (NETA) or placebo. SETTING European clinical gynecology centers. PATIENT(S) Two hundred and nine women with symptomatic fibroids including heavy menstrual bleeding. INTERVENTION(S) Patients received up to four 3-month courses of UPA 10 mg daily, immediately followed by 10-day double-blind treatment with NETA (10 mg daily) or placebo. MAIN OUTCOME MEASURE(S) Amenorrhea, fibroid volume, endometrial histology. RESULT(S) After the first UPA course, amenorrhea occurred in 79% of women, with median onset (from treatment start) of 4 days (interquartile range, 2-6 days). Median fibroid volume change was -45% (interquartile range, -66%; -25%). Amenorrhea rates were 89%, 88%, and 90% for the 131, 119, and 107 women who received treatment courses 2, 3, and 4, respectively. Median times to amenorrhea were 2, 3, and 3 days for treatment courses 2, 3, and 4, respectively. Median fibroid volume changes from baseline were -63%, -67%, and -72% after treatment courses 2, 3, and 4, respectively. All endometrial biopsies showed benign histology without hyperplasia; NETA did not affect fibroid volume or endometrial histology. CONCLUSION(S) Repeated 3-month UPA courses effectively control bleeding and shrink fibroids in patients with symptomatic fibroids. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov (www.clinicaltrials.gov) registration numbers NCT01156857 (PEARL III) and NCT01252069 (PEARL III extension).

Age of menopause and impact of climacteric symptoms by geographical region

Objective To describe differences in the age of onset of menopause and in the prevalence of climacteric symptoms in different geographical areas. Design Systematic review of published data on onset of menopause and symptoms in Europe, North America, Latin America and Asia. Methods We identified publications by searching electronic databases, including MEDLINE (1966–October 2009) and EMBASE (1975–October 2009). Primary search criteria were age of menopause and climacteric symptoms. A sensitive analysis that excluded papers without full data was performed. Results The median age at menopause in Europe ranges from 50.1 to 52.8 years, in North America from 50.5 to 51.4 years, in Latin America from 43.8 to 53 years, and in Asia from 42.1 to 49.5 years. The frequency of vasomotor symptoms varies widely depending on the geographical region, selection of criteria, and method of symptom identification. The prevalence of such symptoms ranges from 74% of women in Europe, 36–50% in North America, 45–69% in Latin America and 22–63% in Asia, as reported in different, large, epidemiological studies. Conclusion There are wide geographical differences in the prevalence of menopausal symptomatology and some differences in the age of onset of menopause. Both in Asia and Latin America, women of poorer socioeconomic status have significantly earlier onset of menopause. Within a geographical region, there are ethnic differences in menopause symptoms. Given differences in study methodologies, firm conclusions are not possible. However, regional differences in age at menopause and in climacteric symptoms are important to acknowledge and lay the foundation for an informed approach to the management of menopause and an understanding of its impact on womens health in the different regions of the world.

Hormonal changes during menopause

Ovarian senescence occurs gradually during the fourth and fifth decades of life, leading to menopause at an average age of about 51 years. This senescence results in a changing hormonal milieu, with decreases in the levels of estrogens and androgens. Similar changes may be induced by surgical menopause (bilateral oophorectomy) or ovarian failure resulting from cancer treatment. The declining levels of estrogens and androgens affect many tissues of the body and can produce a variety of signs and symptoms, including vasomotor symptoms, decreased bone density, changes in mood and energy, loss of pubic hair and changes in the genital tissues, and effects on sexual function. Accurate measurement of testosterone levels in postmenopausal women requires methods that are validated in the lower ranges of testosterone level observed in this population.

Menopausal hot flushes and night sweats: where are we now?

ABSTRACT Objective An overview of the current knowledge on the etiology and treatment of vasomotor symptoms in postmenopausal women. Materials and methods Acknowledged experts in the field contributed a brief assessment of their areas of interest which were combined and edited into the final manuscript. Results Women around the world experience vasomotor symptoms as they enter and complete the menopause transition. Vasomotor symptoms, specifically hot flushes, are caused by a narrowing of the thermoneutral zone in the brain. This effect, although related to estrogen withdrawal, is most likely related to changes in central nervous system neurotransmitters. Peripheral vascular reactivity is also altered in symptomatic women. Estrogen replacement therapy is the most effective treatment for hot flushes. Of the other interventions investigated, selective serotonin and selective norepinephrine reuptake inhibitors and gabapentin show efficacy greater than placebo. Objective monitoring of hot flushes indicates a robust improvement with hormone replacement therapy but little to no change with placebo. These data suggest that the subjective assessment of responses to therapy for vasomotor symptom results in inaccurate data. Hot flushes have recently been associated with increased cardiovascular risks and a lower incidence of breast cancer, but these data require confirmation. Conclusions Vasomotor symptoms are experienced by women of all ethnic groups. They are caused by changes in the central nervous system associated with estrogen withdrawal and are best treated with estrogen replacement therapy. Objective monitoring of hot flushes indicates that placebo has little to no effect on their improvement. Subjective assessments of hot flushes in clinical trials may be inaccurate based on objective measurement of the frequency of hot flushes. Based on preliminary reports, women experiencing hot flushes have an increased risk of cardiovascular disease and a reduced incidence of breast cancer.

Epidemiology of risk factors and symptoms associated with menopause in Spanish women

OBJECTIVES (1) To assess the prevalence of risk factors for osteoporosis and cardiovascular disease and the prevalence and severity of the appearance of menopausal symptoms among Spanish menopausal women. (2) To identify the main factors responsible for this severity. (3) To detect symptom differences between perimenopausal and postmenopausal women. METHODS Cross-sectional descriptive study encompassing women aged 45-65 years in the whole Spanish territory. The study population sample was collected through random sampling. A total of 10,514 women were included. The sociodemographic, medical history and lifestyle data were assessed by means of a survey. The Kupperman scale was used to assess the severity of menopausal symptoms. RESULTS The prevalence of risk factors for osteoporosis and cardiovascular disease were 67.6% and 74.8%, respectively. The most common risk factors were physical inactivity (53.6%), obesity (44.3%), arterial hypertension (36.6%), hypercholesterolemia (31.4%), low calcium intake (30.1%) and smoking (28.7%). The predominant symptoms experienced by menopausal women were hot flushes (51.4%), insomnia (45.7%) and irritability (42.2%). These were severe in 3.3% of the sample, moderate in 27.3%, mild in 24.6% while 44.8% had no symptoms. The prevalence of joint pain (40.1%) and depressive mood (40%) was higher in perimenopausal than in postmenopausal women. Logistic regression analysis showed that there were differences for age, BMI, smoking, social class and poor consumption of dairy products in the severity of menopausal symptoms. CONCLUSIONS A high prevalence of risk factors for osteoporosis and cardiovascular disease was observed in our study. The main factors contributing to more severe menopausal symptoms were age, BMI, smoking social class and poor consumption of dairy products. In general, postmenopausal women presented significantly higher rates of menopausal symptoms when compared to perimenopausal women.

Tolerability of different oral iron supplements: a systematic review.

Abstract Objective: A systematic review was conducted to analyze the tolerability of several oral iron supplements based on data obtained in available publications and to report the incidence of adverse effects (AEs) for each supplement both overall and gastrointestinal. Methods: Electronic databases – Medline, the Cochrane Library, and Embase were searched for studies published up to January 2009. Clinical or observational studies reporting data on the tolerability of oral iron supplements were included. Results were described statistically and a quasi-binomial logistic regression model was developed to evaluate and compare the tolerability of the supplements studied. Results: For this review 111 studies were included, with data on 10,695 patients. Ferrous sulfate with mucoproteose had the lowest incidence of AEs (4.1% for overall AEs, 3.7% for gastrointestinal AEs [GAEs]) and was used as the reference supplement in the regression model. Incidence rates of overall AEs for the other supplements were 7.3% for iron protein succinylate [GAEs: 7%; OR for AE compared to the reference supplement, 1.96], 23.5% for ferrous glycine sulfate [GAEs: 18.5%; OR: 5.90], 30.9% for ferrous gluconate [GAEs: 29.9%; OR: 11.06], 32.3% for ferrous sulfate without mucoproteose [GAEs: 30.2%; OR: 11.21], and 47.0% for ferrous fumarate [GAEs: 43.4%; OR: 19.87]. The differences in incidence of AEs between extended-release ferrous sulfate with mucoproteose and all other supplements except iron protein succinylate were statistically significant at p < 0.001. These findings are subject to some limitations as the designs and methodologies of the studies included show heterogeneity among them that has partially been counteracted by the large sample size provided by the substantial number of trials, which is considered a strength in tolerability studies. Conclusion: Extended-release ferrous sulfate with mucoproteose appears to be the best tolerated of the different oral iron supplements evaluated.

Efficacy and Safety of Strontium Ranelate in the Treatment of Osteoporosis in Men

CONTEXT Strontium ranelate reduces vertebral and nonvertebral fracture risk in postmenopausal osteoporosis. OBJECTIVE The objective of this study was to determine the efficacy and safety of strontium ranelate in osteoporosis in men over 2 years (main analysis after 1 year). DESIGN This was an international, unbalanced (2:1), double-blind, randomized placebo-controlled trial (MALEO [MALE Osteoporosis]). SETTING This international study included 54 centers in 14 countries. PARTICIPANTS PARTICIPANTS were 261 white men with primary osteoporosis. INTERVENTION Strontium ranelate at 2 g/d (n = 174) or placebo (n = 87) was administered. MAIN OUTCOME MEASURES Lumbar spine (L2-L4), femoral neck, and total hip bone mineral density (BMD), biochemical bone markers, and safety were measured. RESULTS Baseline characteristics were similar in both groups in the whole population (age, 72.9 ± 6.0 years; lumbar spine BMD T-score, -2.7 ± 1.0; femoral neck BMD T-score, -2.3 ± 0.7). Men who received strontium ranelate over 2 years had greater increases in lumbar spine BMD than those who received placebo (relative change from baseline to end, 9.7% ± 7.5% vs 2.0% ± 5.5%; between-group difference estimate (SE), 7.7% (0.9%); 95% confidence interval, 5.9%-9.5%; P < .001). There were also significant between-group differences in relative changes in femoral neck BMD (P < .001) and total hip BMD (P < .001). At the end of treatment, mean levels of serum cross-linked telopeptides of type I collagen, a marker of bone resorption, were increased in both the strontium ranelate group (10.7% ± 58.0%; P = .022) and the placebo group (34.9% ± 65.8%; P < .001). The corresponding mean changes of bone alkaline phosphatase, a marker of bone formation, were 6.4% ± 28.5% (P = .005) and 1.9% ± 25.4% (P = .505), respectively. After 2 years, the blood strontium level (129 ± 66 μmol/L) was similar to that in trials of postmenopausal osteoporosis. Strontium ranelate was generally well tolerated. CONCLUSIONS The effects of strontium ranelate on BMD in osteoporotic men were similar to those in postmenopausal osteoporotic women, supporting its use in the treatment of osteoporosis in men.

Changes in sex behaviour after menopause: effects of tibolone.

In order to analyse both sexual desire after menopause and its response to treatment with tibolone, a randomized placebo/tibolone trial has been designed with 28 postmenopausal patients. They were asked to answer a questionnaire designed by us to obtain quantitative measurements to describe changes in sexual desire. After selection, the patients were randomly assigned to two groups as follows: 14 in the group treated with 2.5 mg/day of tibolone and 14 in the placebo group treated with 500 mg/day of calcium. The patients were monitored after 3, 6 and 12 months. Before joining this study, they had signed a written consent. It was observed that the sexual desire after menopause underwent a significant fall, with decline in arousability and intercourse. The comparative results show that the patients treated with tibolone experience an improvement after the third month of treatment and this improvement was maintained until the end of treatment. We conclude that the questionnaire proposed here is a useful non-parametric method to diagnose a patients sexuality status at the baseline assessment and a valuable tool for monitoring various therapies. Furthermore, tibolone proved to be effective in managing reduced sexual desire which appears in postmenopausal patients.

Safety of bazedoxifene in a randomized, double-blind, placebo- and active-controlled phase 3 study of postmenopausal women with osteoporosis

BackgroundWe report the safety findings from a 3-year phase 3 study (NCT00205777) of bazedoxifene, a novel selective estrogen receptor modulator under development for the prevention and treatment of postmenopausal osteoporosis.MethodsHealthy postmenopausal osteoporotic women (N = 7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. Safety and tolerability were assessed by adverse event (AE) reporting and routine physical, gynecologic, and breast examination.ResultsOverall, the incidence of AEs, serious AEs, and discontinuations due to AEs in the bazedoxifene groups was not different from that seen in the placebo group. The incidence of hot flushes and leg cramps was higher with bazedoxifene or raloxifene compared with placebo. The rates of cardiac disorders and cerebrovascular events were low and evenly distributed among groups. Venous thromboembolic events, primarily deep vein thromboses, were more frequently reported in the active treatment groups compared with the placebo group; rates were similar with bazedoxifene and raloxifene. Bazedoxifene showed a neutral effect on the breast and an excellent endometrial safety profile. The incidence of fibrocystic breast disease was lower with bazedoxifene 20 and 40 mg versus raloxifene or placebo. Reductions in total and low-density lipoprotein levels and increases in high-density lipoprotein levels were seen with bazedoxifene versus placebo; similar results were seen with raloxifene. Triglyceride levels were similar among groups.ConclusionBazedoxifene showed a favorable safety and tolerability profile in women with postmenopausal osteoporosis.Trial RegistrationTrial registration number: NCT00205777; Trial registration date: September 16, 2005

Ospemifene, a non-oestrogen selective oestrogen receptor modulator for the treatment of vaginal dryness associated with postmenopausal vulvar and vaginal atrophy: A randomised, placebo-controlled, phase III trial

OBJECTIVE To evaluate the efficacy and safety of ospemifene, a novel selective oestrogen receptor modulator, in the treatment of vaginal dryness in postmenopausal women with vulvovaginal atrophy (VVA). STUDY DESIGN A 12 week, multicentre, randomised, double-blind, parallel-group phase III study of women (40-80 years) with VVA and self-reported vaginal dryness as their most bothersome symptom. MAIN OUTCOME MEASURES The co-primary efficacy endpoints were the change from baseline to Week 12 in (1) percentage of parabasal cells in the maturation index (MI), (2) percentage of superficial cells in the MI, (3) vaginal pH, and (4) severity of vaginal dryness. Safety assessments included physical examination, cervical Papanicolaou test and clinical laboratory analyses. Endometrial thickness and histology was also assessed. RESULTS A total of 314 women were randomised to once-daily ospemifene 60 mg/day (n=160) or placebo (n=154). Significant improvements in the percentages of parabasal and superficial cells in the MI and vaginal pH were observed with ospemifene compared with placebo (p<0.001 for all parameters). The mean change from baseline in severity score of vaginal dryness reported by women receiving ospemifene compared with those receiving placebo approached statistical significance (p=0.080). Improvements in each of the four co-primary endpoints with ospemifene were statistically significant compared to placebo in the per protocol population. The majority of treatment-emergent adverse events were considered mild to moderate in severity. CONCLUSIONS Once-daily oral ospemifene 60 mg was effective for the treatment of VVA in postmenopausal women with vaginal dryness.