Semana del 27 de Septiembre al 3 de Octubre de 2006
Dr. Juan Enrique Blümel
Pol Merkuriusz Lek. 2006 Jun;20(120):727-30
Sex hormones and adipocytokines in postmenopausal women
Sieminska L, Cichon-Lenart A, Kajdaniuk D, Kos-Kudla B, Marek B, Lenart J, Nowak M.
Slaska Akademia Medyczna w Zabrzu, Katedra Patofizjologii i Endokrynologii. lusiem@poczta.onet.pl
Visceral fat accumulation occuring in postmenopausal women is connected with hypoestrogenism, decreased production of sex-hormone binding globuline (SHBG) and with rise in free testosterone. They have been identified as risk factors for cardiovascular diseases. The exact mechanisms mediating relationships between the excess of visceral adiposity, hormonal variations after menopause and metabolic disturbances, remain unknown. We speculate that adipocytokines produced by adipose tissue: adiponectin, leptin and resistin, might play a role. Adiponectin is a hormone which plays a role in insulin sensitivity and lipid oxidation, and possesses anti-inflammatory properties. Increased levels of androgens post menopause and low SHBG are connected with decreased production of adiponectin. Leptin is another of the adipocytokines which has been shown to be linked to insulin resistance, increased pressure and hypertriglyceridaemia. Sex steroids have effect on leptin secretion but the associations between leptin and menopause are controversial. Recently it was found that resistin, another bioactive substance produced by adipose tissue may related to insulin resistance. Studies on animals indicate that ovariectomy and testosterone significantly increased resistin expression. It seems that adipocytokines may be a link connecting postmenopasual hormonal changes, the excess of visceral fat and increased risk of cardiovascular diseases.
Menopause. 2006 Sep 26; [Epub ahead of print]
Tibolone for the treatment of moderate to severe vasomotor symptoms and genital atrophy in postmenopausal women: a multicenter, randomized, double-blind, placebo-controlled study.
Swanson SG, Drosman S, Helmond FA, Stathopoulos VM.
From the 1Women's Clinic of Lincoln, Lincoln, NE; 2Genesis Center for Clinical Research, San Diego, CA; and Organon International, Roseland, NJ.
OBJECTIVE:: To demonstrate the safety and efficacy of tibolone (1.25 and 2.5 mg) in the treatment of moderate to severe vasomotor symptoms and symptoms associated with vaginal atrophy. DESIGN:: A placebo-controlled, double-blind, randomized, multicenter study was conducted on 396 healthy postmenopausal women experiencing a minimum of 7 moderate to severe hot flashes per day (60 per week). Participants were randomized to receive tibolone 1.25 or 2.5 mg or placebo once daily for 12 weeks. Assessments were done at weeks 4, 8, and 12. The severity and frequency of hot flashes were recorded in patient diaries on a daily basis. RESULTS:: Tibolone 2.5 mg significantly (P < 0.001) reduced the average number of hot flashes compared with placebo at week 4 (-7.82 vs -5.27), week 8 (-9.71 vs -5.86), and week 12 (-10.14 vs -5.85). The difference between tibolone 1.25 mg and placebo was significant (P < 0.001) at week 8 (-7.96) and week 12 (-8.32). Findings for the average daily severity of hot flashes were similar, with significantly greater reductions at week 4 (P < 0.05) and weeks 8 and 12 (P < 0.001) for tibolone 2.5 mg versus placebo and at weeks 8 and 12 for tibolone 1.25 mg versus placebo (P < 0.001). A menopausal atrophic symptom questionnaire revealed that tibolone 2.5 mg significantly (P < 0.05) reduced nocturia compared with placebo at weeks 4, 8, and 12 and urinary urgency at week 4. Compared with placebo, both doses of tibolone also significantly (P < 0.001) increased the vaginal maturation value from baseline. The overall incidence of adverse events was similar in all treatment groups. CONCLUSIONS:: Tibolone is effective and well tolerated for the treatment of moderate to severe vasomotor symptoms and the effects of vaginal atrophy associated with menopause.
Menopause. 2006 Sep 20; [Epub ahead of print]
Sexual functioning throughout menopause: the perceptions of women in a British cohort.
Mishra G, Kuh D.
From the Medical Research Council National Survey of Health and Development, University College and Royal Free Medical School, London, United Kingdom.
OBJECTIVE:: Previous studies on menopausal transition and sexual functioning have mixed findings. Most are cross-sectional, exclude hormone therapy users and hysterectomized women, and are unable to separate the effects of age from menopause or account for psychosocial, vasomotor, and somatic factors. We examine relationships between women's reports of a change in sex life and difficulties with intercourse and their experience of menopausal transition, use of hormone therapy, and hysterectomy. DESIGN:: A British cohort study with 1,525 women were followed since their birth in 1946 and annually from age 47 to 54 years. The outcome measures were self-reported change in sex life and difficulties with sexual intercourse over 8 consecutive years. RESULTS:: Compared with women who remained premenopausal, peri- and postmenopausal women reported a decline in sex life (mean difference [95% CI]: perimenopausal, -0.1 [-0.2 to -0.03]; became postmenopausal, -0.1 [-0.2 to -0.1]) and were more likely to report difficulties with intercourse (perimenopausal, 0.6 [0.1 to 1.1]; postmenopausal, 1.0 [0.5 to 1.5]) beyond the effects of aging and other psychosomatic factors. Women reported difficulties with intercourse more often if they had been on hormone therapy for more than a year (0.5 [0.03 to 1.0]) or if they had undergone a hysterectomy (0.6 [0.1 to 1.1]); no differences were found for change in sex life. For both outcomes, vaginal dryness was the major risk factor. Married women were also more likely to report adverse outcomes. Somatic symptoms and hot flushes/cold sweats were associated with difficulties with intercourse, whereas psychological symptoms, stressful lives, increasing age, and smoking were associated with a decline in sex life. CONCLUSIONS:: Menopausal transition status had an independent effect on the reported change in sex life and difficulties with intercourse. The results support health professionals in their development of management strategies that (a) consider treatments directly for vaginal dryness, (b) identify somatic symptoms for difficulties with intercourse, (c) investigate psychological factors for a reported decline in sex life, and (d) for both outcomes, consider the potential role of intimate partners.
Proc Natl Acad Sci U S A. 2006 Sep 26; [Epub ahead of print]
Follicle-stimulating hormone stimulates TNF production from immune cells to enhance osteoblast and osteoclast formation.
Iqbal J, Sun L, Kumar TR, Blair HC, Zaidi M.
Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, New York, NY
Declining estrogen production after menopause causes osteoporosis in which the resorption of bone exceeds the increase in bone formation. We recently found that mice deficient in the beta-subunit of follicle-stimulating hormone (FSHbeta) are protected from bone loss despite severe estrogen deficiency. Here we show that FSHbeta-deficient mice have lowered TNFalpha levels. However, TNFalpha-deficient mice are resistant to hypogonadal bone loss despite having elevated FSH, suggesting that TNFalpha is critical to the effect of FSH on bone mass. We find that FSH directly stimulates TNFalpha production from bone marrow granulocytes and macrophages. We also explore how TNFalpha up-regulation induces bone loss. By modeling the known actions of TNFalpha, we attribute the high-turnover bone loss to an expanded osteoclast precursor pool, together with enhanced osteoblast formation. TNFalpha inhibits osteoblastogenesis in the presence of ascorbic acid in culture medium, but in its absence this effect becomes stimulatory; thus, ascorbic acid reverses the true action of TNFalpha. Likewise, ascorbic acid blunts the effects of TNFalpha in stimulating osteoclast formation. We propose that hypogonadal bone loss is caused, at least in part, by enhanced FSH secretion, which in turn increases TNFalpha production to expand the number of bone marrow osteoclast precursors. Ascorbic acid may prevent FSH-induced hypogonadal bone loss by modulating the catabolic actions of TNFalpha.
Indian J Pathol Microbiol. 2006 Jul;49(3):457-61.
Vaginal microflora in postmenopausal women on hormone replacement therapy.
Gupta S, Kumar N, Singhal N, Kaur R, Manektala U.
Institute of Cytology and Preventive Oncology, New Delhi. sanjaydr17@hotmail.com
To study the spectrum of vaginal microflora in postmenopausal women on hormone replacement therapy (HRT) and to compare the efficacy of Papanicolaou (Pap) smears with other methods for their detection. Eighty postmenopausal women were recruited for the study. These included 40 women who had attained spontaneous and were on HRT (User 1); 20 hysterectomised women on only estrogen therapy (User 2) and 20 controls (Non users). Their clinical data was recorded and specimens were collected for vaginal cultures (for aerobic bacteria and fungi), vaginal pH, Gram stain and Pap stain on cervical-vaginal smears and toluidine blue on wet smears. Vaginal pH was significantly lower in Users as compared to Non users. Lactobacilli and Gardnerella were more frequently isolated from Users while Bacteroides and E. coli were more common in Non users. Cultures were significantly more sensitive than Gram stained direct vaginal smears in detection of aerobic bacteria; however, Candida could be detected on Gram stain alone in all the cases. Frequency of detection of organisms significantly improved by application of Gram stain to the cervico-vaginal smears. However, clinically relevant organisms like Candida, Gardnerella and Mobiluncus could be identified on Pap smears alone in >50% cases. Lactobacilli could be readily identified in Pap smears in 98% cases. Wet mounts could detect cocci more easily as compared to Pap smears. Altered vaginal microbial profile in post menopausal women receiving HRT may cause bacterial and fungal vaginitis. Although culture studies remain the gold standard to detect these microorganisms, Pap and Gram stains and wet smears provide useful supplements and may be used as alternative procedures especially in resource limited settings lacking adequate culture facilities.
Climacteric. 2006 Oct;9(5):380-7
The dilemma of menopause and hormone replacement - a challenge for women and health-care providers: knowledge of menopause and hormone therapy in Spanish menopausal women.
Castelo-Branco C, Peralta S, Ferrer J, Palacios S, Cornago S, Quereda F.
Gynecology, Obstetrics and Neonatology Institute, Hospital Clinic Barcelona, Faculty of Medicine, University of Barcelona, Barcelona.
Background An important goal in menopause research is to develop knowledge and identify interventions that strive to promote, maintain and enhance well-being for women.Objective To evaluate the knowledge of postmenopausal Spanish women about menopause and their knowledge of and trust in hormone replacement therapy (HRT) and to identify their sources of information and how those data are related to compliance with their prescription.Study design A total of 270 symptomatic postmenopausal women were personally interviewed using a structured questionnaire, which was designed to collect information on their familiarity with medical menopause studies, the menopause and the effects of HRT, their knowledge of alternative therapies, and to identify their sources of information.Results The most well-known menopausal complaints were hot flushes, sweats, irregular menstruation, cessation of menstruation, irritability and mood changes. Following suggestions of other symptoms by the interviewer, other complaints such as vaginal dryness, insomnia and depression/anxiety were also mentioned. HRT and phytoestrogens were recognized as treatments for the climacteric by most of the women. A woman's decision to seek treatment was initiated in 77% of cases by the gynecologist, in 12% by the general practitioner, in 3% by friends/family and in 3% by books/magazines. The most frequent responses of women to the onset of menopausal symptoms were to talk with their partner (39%), to discuss it with their gynecologist (33%) or with their general practitioner (14%) and to talk with their friends/family or to read books/magazines (10%).Conclusions Vasomotor symptoms are recognized as the main complaint during the climacteric and HRT and phytoestrogens as the main therapies. Gynecologists play an important role in assuring compliance with therapies related to the menopause.
Climacteric. 2006 Oct;9(5):325-35.
Hormone replacement therapy in women with past history of endometriosis.
Soliman NF, Hillard TC.
Yeovil Hospital, Higher Kingston, Yeovil, UK.
Endometriosis is a common clinical condition and its treatment will often lead to an estrogen deficiency status. As most of these patients are young, they will need to consider hormone replacement therapy. Endometriosis is a hormone-dependent disease and estrogen replacement can be associated with a risk of recurrence or malignant transformation. Only a few studies have addressed this problem. With the use of hormone replacement therapy (HRT), there is an increased, although undefined, risk of recurrence of endometriosis, especially in known severe cases and in obese patients. Unopposed estrogen appears to carry a higher risk than combined preparations. Delay in starting HRT after pelvic clearance is not of any benefit. After radical surgery for severe endometriosis, women often have much to gain from HRT, particularly in the early years. Benefits of HRT in terms of control of menopausal symptoms, prevention of urogenital atrophy and loss of libido and bone protection are of particular importance. HRT may still have a role in prevention of cardiovascular disease in early menopause, but this remains unproven. Although there is no firm evidence, continuous combined preparations or tibolone would appear to be the optimum choice.
J Womens Health (Larchmt). 2006 Sep;15(7):857-61
Escitalopram for perimenopausal depression: an open-label pilot study.
Freeman MP, Hill R, Brumbach BH.
Women's Mental Health Program, Departments of Psychiatry, Obstetrics and Gynecology, and Nutritional Sciences, University of Arizona College of Medicine, Tucson, Arizona.
Background: Women have a relatively high risk of experiencing depressive episodes during the perimenopause. Indications for and acceptance of hormone replacement therapy (HRT) are increasingly controversial, and serotonin reuptake inhibitor antidepressants are an attractive potential treatment option for both the mood and somatic symptoms of perimenopause. Methods: This study is an open-label, 8-week trial of escitalopram for perimenopausal depression and somatic symptoms associated with perimenopause. Twenty women received escitalopram and were serially assessed with the Hamilton Rating Scale for Depression (HAMD, 30-item), the Greene Climacteric Scale (GCS), and the Clinical Global Impression (CGI). Results: There were significant differences between pretest and posttest scores for each measure, as demonstrated in an intent-to-treat analysis: GCS (p < 0.0001), HAM-D30 (p < 0.0001), and CGI (p < 0.0001). Two subjects dropped out prior to the second visit because of drug side effects. In this study, benefits of treatment were observed in several domains of perimenopausal symptoms, including those representative of psychological, vasomotor, and somatic symptoms. The limitations of this study are small sample size and lack of placebo control. Conclusions: Larger, long-term, controlled trials of antidepressants are warranted for the treatment of perimenopausal depression and associated somatic symptoms.
J Womens Health (Larchmt). 2006 Sep;15(7):836-42.
Obesity Distribution and Reproductive Hormone Levels in Women: A Report from the NHLBI-Sponsored WISE Study.
Olson MB, Shaw LJ, Kaizar EE, Kelsey SF, Bittner V, Reis SE, Smith K, Braunstein GD, Berga SL, Johnson BD, Merz CN.
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
Purpose: Relationships between body weight and disease are not straightforward. Central obesity appears to be a relatively greater cardiovascular risk factor than generalized obesity. The purpose of this study was to evaluate body mass index (BMI) and waist circumference and the association of obesity distribution with blood estrogen levels (estradiol, bioavailable estradiol, and estrone). Methods: The study cohort consisted of 207 postmenopausal women enrolled in the Women's Ischemia Syndrome Evaluation (WISE) undergoing angiography for evaluation of suspected ischemia. Results: Both BMI and waist circumference were positively associated with all three blood estrogen levels (p < 0.01), with the highest estrogen levels found in the obese women with large waists (p < 0.01). Results from regression analyses confirmed significant associations of BMI and waist circumference with the estrogen levels. Conclusions: These results demonstrate differing relationships between blood estrogen levels and obesity distribution in a cohort of postmenopausal women with chest pain undergoing coronary angiography. The differing levels by general and central obesity may help explain in part observed epidemiological relationships between obesity and disease.
Int J Cancer. 2006 Sep 22; [Epub ahead of print]
Use of hormone replacement therapy before and after ovarian cancer diagnosis and ovarian cancer survival.
Mascarenhas C, Lambe M, Bellocco R, Bergfeldt K, Riman T, Persson I, Weiderpass E.
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
Use of hormone replacement therapy (HRT) has been hypothesized to affect survival of epithelial ovarian cancer (EOC). We studied 5-year survival in patients with invasive EOC and borderline ovarian tumors (BOT) according to HRT use before and after diagnosis in a prospective nation-wide cohort study of 799 women diagnosed with EOC (n = 649) and BOT (n = 150) aged 50-74 years in 1993-1995 in Sweden. Cox regression was used to obtain multivariate age-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Multivariate models included indicator variables for age, tumor stage, grade and histological subtype. After 5 years of follow-up, 45% of the patients with EOC and 93% of the patients with BOT were alive. For women with BOT there were no associations between HRT-use pre- or postdiagnosis and survival. There was no overall difference in 5-year EOC survival according to use HRT before diagnosis (multivariate HR = 0.83, 95% CI = 0.65-1.08), except for serous EOC (HR = 0.69, 95% CI = 0.48-0.98). Analyses of different HRT preparations, duration and recency of use did not reveal any variations in pattern of survival. We observed a better survival for EOC-patients who used HRT after diagnosis (multivariate HR = 0.57, 95% CI = 0.42-0.78). We conclude that HRT-use prior to diagnosis of EOC does not affect 5-year survival, except for a possible survival advantage in serous EOC. Women using HRT after diagnosis had a better survival than women with no use, but we cannot rule out that this latter finding may reflect a subtle selection process.
Am J Epidemiol. 2006 Sep 22; [Epub ahead of print]
Case-Control Study of Postmenopausal Hormone Replacement Therapy and Endometrial Cancer.
Strom BL, Schinnar R, Weber AL, Bunin G, Berlin JA, Baumgarten M, Demichele A, Rubin SC, Berlin M, Troxel AB, Rebbeck TR.
Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA
This study evaluated recent inconsistent findings that adding progestins to postmenopausal estrogen replacement therapy protects against endometrial cancer. Using a population-based case-control study, the authors compared 511 endometrial cancer cases aged 50-79 years in the Philadelphia, Pennsylvania, region during 1999-2002 with 1,412 random-digit-dialing controls regarding postmenopausal hormone replacement therapy (HRT) use. Telephone interviews were performed with memory aids mailed in advance. An increased risk of endometrial cancer was observed among postmenopausal women using only unopposed estrogen for 3 or more years, compared with women who never used HRT (adjusted odds ratio = 3.4, 95% confidence interval (CI): 1.4, 8.3). Using combination HRT (of any duration) was associated with a substantial reduction in risk (odds ratio = 0.8, 95% CI: 0.6, 1.1). Comparing women using only combined estrogen and progestin for 3 or more years with women using only unopposed estrogen for 3 or more years, the authors found that the adjusted odds ratio was 0.2 (95% CI: 0.1, 0.6). Long-term use of unopposed estrogen is associated with increased risk for endometrial cancer, whereas combined estrogen plus progestin hormone therapy is not. Thus, if HRT is to be used in women with an intact uterus, this study confirms the benefit of adding progestins to the regimen.
J Bone Miner Res. 2006 Oct;21(10):1565-70
Fracture Incidence and Characterization in Patients on Osteoporosis Treatment: The ICARO Study.
Adami S, Isaia G, Luisetto G, Minisola S, Sinigaglia L, Gentilella R, Agnusdei D, Iori N, Nuti R; on behalf of ICARO Study Group.
None of the available osteoporosis therapies have been shown to completely abolish the risk of fractures. In clinical practice, the outcome may be even poorer. In 880 patients prescribed with antiresorptives (alendronate, risedronate, and raloxifene) for >1 year, a fragility fracture was recorded in 8.9%/year of them. This incidence is considerably higher than that observed in randomized clinical trials, and it was significantly related to poor compliance and lack of supplementation with calcium and vitamin D. Introduction: Osteoporotic fracture is one of the most important public health concerns among the elderly. Currently available therapies have been shown to significantly decrease the risk of fracture, although none of them completely abolishes this risk. In clinical practice, poor treatment response may also result from a number of other factors. Materials and Methods: The Incidence and ChAracterization of inadequate clinical Responders in Osteoporosis (ICARO) is a multicenter, observational study carried out in Italy. It aimed to analyze, in postmenopausal women with established osteoporosis, the risk factors for an "inadequate clinical response" to drug therapy, defined as the occurrence of new vertebral or nonvertebral fragility fractures in patients prescribed, for at least 1 year, alendronate, risedronate, or raloxifene, with a compliance >50%. Results: In 880 patients treated with antiresorptive agents for a median of 2.0 years (95% CI: 1.0-4.5) years, the "inadequate clinical responder (ICR)" subjects over the observation period were 220 (25%), with an annual incidence of 8.9%. ICRs, compared with "adequate clinical responders (ACRs)," had more pretreatment fractures and were treated longer (2.8 versus 1.8 years; p < 0.001). After multiple adjustment for these confounding factors, significant determinants of inadequate clinical response were a poorer treatment compliance and a less frequent co-administration of calcium and vitamin D supplements. Conclusions: The incidence of fractures during treatment with antiresorptive agents in a clinical setting is considerably higher than that observed in randomized clinical trials. Inadequate compliance to treatment and lack of supplementation of calcium and vitamin D are major determinants of this poor response.
Semana del 30 de Agosto al 4 de Septiembre de 2006
Dr. Juan Enrique Blümel
Lancet. 2006 Aug 19;368(9536):647-58
Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case-control study.
Teo KK, Ounpuu S, Hawken S, Pandey MR, Valentin V, Hunt D, Diaz R, Rashed W, Freeman R, Jiang L, Zhang X, Yusuf S; INTERHEART Study Investigators.
Population Health Research Institute, McMaster University-Hamilton Health Sciences, Hamilton, ON L8L 2X2, Canada.
BACKGROUND: Tobacco use is one of the major avoidable causes of cardiovascular diseases. We aimed to assess the risks associated with tobacco use (both smoking and non-smoking) and second hand tobacco smoke (SHS) worldwide. METHODS: We did a standardised case-control study of acute myocardial infarction (AMI) with 27,089 participants in 52 countries (12,461 cases, 14,637 controls). We assessed relation between risk of AMI and current or former smoking, type of tobacco, amount smoked, effect of smokeless tobacco, and exposure to SHS. We controlled for confounders such as differences in lifestyles between smokers and non-smokers. FINDINGS: Current smoking was associated with a greater risk of non-fatal AMI (odds ratio [OR] 2.95, 95% CI 2.77-3.14, p<0.0001) compared with never smoking; risk increased by 5.6% for every additional cigarette smoked. The OR associated with former smoking fell to 1.87 (95% CI 1.55-2.24) within 3 years of quitting. A residual excess risk remained 20 or more years after quitting (1.22, 1.09-1.37). Exclusion of individuals exposed to SHS in the never smoker reference group raised the risk in former smokers by about 10%. Smoking beedies alone (indigenous to South Asia) was associated with increased risk (2.89, 2.11-3.96) similar to that associated with cigarette smoking. Chewing tobacco alone was associated with OR 2.23 (1.41-3.52), and smokers who also chewed tobacco had the highest increase in risk (4.09, 2.98-5.61). SHS was associated with a graded increase in risk related to exposure; OR was 1.24 (1.17-1.32) in individuals who were least exposed (1-7 h per week) and 1.62 (1.45-1.81) in people who were most exposed (>21 h per week). Young male current smokers had the highest population attributable risk (58.3%; 95% CI 55.0-61.6) and older women the lowest (6.2%, 4.1-9.2). Population attributable risk for exposure to SHS for more than 1 h per week in never smokers was 15.4% (12.1-19.3). CONCLUSION: Tobacco use is one of the most important causes of AMI globally, especially in men. All forms of tobacco use, including different types of smoking and chewing tobacco and inhalation of SHS, should be discouraged to prevent cardiovascular diseases.
Swiss Med Wkly. 2006 Aug 5;136(31-32):510-4
Antioxidant effects of hormone replacement therapy in postmenopausal women.
Delibasi T, Kockar C, Celik A, Kockar O.
Ankara Numune Hospital, Department of Endocrinology and Metabolism, Ankara, Turkey. tuncay@delibasi.net.
QUESTIONS UNDER STUDY: Postmenopausal women are more likely to develop coronary artery disease than premenopausal women of the same age. Postmenopausal oral oestrogen therapy is associated with increased levels of high-density lipoprotein (HDL) cholesterol and decreased levels of lowdensity lipoprotein (LDL) cholesterol. In this study we investigated the direct contribution of hormone replacement therapy on total antioxidant capacity rather than its effects on the serum lipid profile. METHODS: At the time of enrolment and after the drug delivery plasma total cholesterol, triglycerides (TG), HDL, LDL, uric acid, total bilirubin, albumin, oestradiol levels and total antioxidant capacity of plasma were assessed. RESULTS: Levels of plasma TG and total antioxidant capacity were significantly increased in the study group. CONCLUSIONS: Our results suggest that oestrogen has an antioxidant effect following 3 months of hormone replacement therapy. Progesterone in combination with oestrogen does not have this effect. Also plasma TG levels increased in those patients receiving HRT after 3 months.
Menopause. 2006 Aug 28; [Epub ahead of print]
Hormone therapy and cerebrovascular events: a population-based nested case-control study.
Arana A, Varas C, Gonzalez-Perez A, Gutierrez L, Bjerrum L, Garcia Rodriguez LA.
From the 1Novartis, Clinical Safety and Epidemiology; 2Centro Espanol de Investigacion Farmacoepidemiologica (CEIFE), Madrid, Spain; and 3Research Unit of General Practice, University of Southern Denmark, Odense, Denmark.
OBJECTIVE:: The relationship between postmenopausal hormone therapy (HT) and cerebrovascular disease has been examined in several epidemiological studies and clinical trials with conflicting results. The authors aimed to evaluate the association between the use of HT and the incidence of first cerebrovascular event. DESIGN:: The study cohort comprised 158,031 women 50 to 69 years old registered in the U.K. General Practice Research Database between 1991 and 1997. The authors conducted a nested case-control analysis using all 920 confirmed cases of cerebrovascular events identified during the follow-up (536 of transient ischemic attack [TIA]; 259 of ischemic stroke; 125 of hemorrhagic stroke) and 10,000 controls. RESULTS:: The odds ratios of TIA, ischemic stroke, and hemorrhagic stroke among women currently using HT were 1.48 (95% CI, 1.17-1.87), 1.12 (95% CI, 0.78-1.59) and 1.21 (95% CI, 0.76-1.93), respectively, compared to never users. The overall risk estimate for having a cerebrovascular event was 1.34 (95% CI, 1.11-1.61). The risk of TIA was greater (1.96) among women using high doses of estrogen (95% CI, 1.34-2.87). CONCLUSION:: Overall, a small increased risk of stroke associated with HT use of comparable magnitude to the one observed in recent clinical trials was found. The increased risk was more apparent for TIA than for stroke and was greater at higher doses.
Menopause. 2006 Aug 28; [Epub ahead of print]
A randomized comparative study of the effects of oral and topical estrogen therapy on the vaginal vascularization and sexual function in hysterectomized postmenopausal women.
Long CY, Liu CM, Hsu SC, Wu CH, Wang CL, Tsai EM.
From the 1Department of Obstetrics and Gynecology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Department of Obstetrics and Gynecology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; and 3Department of Obstetrics and Gynecology, Kaohsiung Medical University, Chung-Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
OBJECTIVE:: To compare the effects of oral and vaginal estrogen therapy (ET) on the vaginal blood flow and sexual function in postmenopausal women with prior hysterectomy. DESIGN:: Fifty-seven women were randomized to receive either oral (0.625 mg of conjugated equine estrogen per tablet; n = 27) or topical (0.625 mg conjugated equine estrogen per 1 g vaginal cream; n = 30) estrogen administered once daily. All subjects had estradiol measurements, urinalysis, pelvic examination, introital color Doppler ultrasonographies and personal interviews for sexual symptoms using a validated questionnaire before and 3 months after ET. RESULTS:: A higher serum level of estradiol was noted in the oral group compared to the topical group following 3 months of ET. There were significant increases in the number of vaginal vessels and the minimum diastole (P < 0.01), and marked decreases of pulsatility index (PI) values (P < 0.01) in both groups after ET. Regarding the systolic peak, we found a significant decrease only in the topical group (P < 0.05). Although the post-ET prevalence of anorgasmia decreased significantly in both groups (P < 0.05), changes in other domains, including the rates of low libido and coital frequency, were not statistically significant (P > 0.05). In the topical group, ET improves sexual function on the vaginal dryness and dyspareunia domains in a statistically significant manner (P < 0.05), but this is not the case in the oral group (P > 0.05). However, the efficacies of oral ET for vaginal dryness and dyspareunia reached 80% and 70.6%, respectively. The corresponding figures of the topical ET were 79.2% and 75%. CONCLUSIONS:: The results of our study suggests that ET alone in hysterectomized postmenopausal women increases the vaginal blood flow and improves some domains of sexual function, but it may not have impact on diminished sexual desire or activity. Compared with systemic therapy, topical vaginal preparations are found to correlate with better symptom relief despite the lower serum level of estradiol.
Am J Physiol Regul Integr Comp Physiol. 2006 Aug 31; [Epub ahead of print]
Effect of Ageing on the Cardiovascular Regulatory Systems in Healthy Women.
Lavi S, Nevo O, Thaler I, Rosenfeld R, Dayan L, Hirshoren N, Gepstein L, Jacob G.
Cardiology, Rambam Medical Center, J. Recanati Autonomic Dysfunction Center, Israel.
Ageing, independently from the hormonal status, is a major risk factor for cardiovascular morbidity in healthy women. Therefore, we studied the effect of healthy ageing on the cardiovascular homeostatic mechanisms in premenopausal and postmenopausal women with similar estrogen levels. Twelve healthy postmenopausal women, confirmed by FSH and LH levels, were compared to 14 normally menstruating women during the early follicular phase (young-EF), in order to avoid as much as possible the effects of estrogen. Systolic BP was 108+/-1.5 vs. 123+/-2.5 (p<0.001), supine norepinephrine was 260+/-30 vs. 216+/-45 and upright 640+/-100 vs. 395+/-50 pg/ml (p=0.05) in young-EF vs. postmenopausal, respectively. Plasma renin activity and aldosterone remained unchanged. Vagal cardiac tone indices decreased significantly with ageing (young-EF vs. postmenopausal): Hf band, rMSSD and PNN50% were 620+/-140 vs. 270+/-70 (p=0.04), 53+/-7 vs. 30+/-3 (p=0.02), and 23+/-5 vs. 10+/-3 (p=0.04), respectively. Lf to Hf ratio was 0.85+/-0.17 in young-EF and became 1.5+/-0.22 in postmenopausal (p=0.03). Both arms of the baroreflex, +BRS (29+/-5 vs. 13.5+/-2.5, p=0.01) and -BRS (26+/-4 vs. 15+/-1.5, p=0.02) decreased with ageing. Cardiovascular alpha1-adrenoreceptor responsiveness significantly increased and beta-decreased, in postmenopausal compared to young-EF (p<0.001, both). The QTc intervals were similar, whereas JTc and JTc to QTc ratio were prolonged in the postmenopausal group. We conclude that in young women, parasympathetic control is the main regulator of the cardiovascular system and in postmenopausal women sympathetic tone dominants. The transition from parasympathetic to sympathetic control may contribute to the increased cardiovascular morbidity with ageing. Key words: Autonomic nervous system, baroreflex, women, renin, ageing.
Am J Med. 2006 Sep;119(9):777-85
Randomized controlled trial of calcium in healthy older women.
Reid IR, Mason B, Horne A, Ames R, Reid HE, Bava U, Bolland MJ, Gamble GD.
Department of Medicine, University of Auckland, Auckland, New Zealand. i.reid@auckland.ac.nz
PURPOSE: Calcium has been shown to have positive effects on bone mineral density in postmenopausal women. However, these effects are small, it is unknown whether they are sustained with long-term use, they have not been shown with intention-to-treat analyses, and the evidence for fracture prevention with calcium monotherapy is inconsistent. METHODS: A randomized controlled trial of calcium (1 g/day as the citrate) in 1471 healthy postmenopausal women (aged 74+/-4 years) was performed to assess the effects on bone density and fracture incidence over 5 years. RESULTS: Follow-up was complete in 90% of subjects, and average medication compliance was 55% to 58%. Calcium had a significant beneficial effect on bone density (intention-to-treat analysis), with between-groups differences at 5 years of 1.8% (spine), 1.6% (total hip), and 1.2% (total body). Effects were greater in a per-protocol analysis (5-year differences of 2.3%, 2.8%, and 1.8%, respectively). A total of 425 fractures occurred in 281 women. Hazard ratios, based on time to first fracture, were 0.90 (95% confidence interval [CI], 0.71-1.16) for any symptomatic fracture, 0.72 (95% CI, 0.44-1.18) for vertebral, 3.55 (95% CI, 1.31-9.63) for hip, and 0.65 (95% CI, 0.41-1.04) for forearm fracture. Per-protocol analysis found respective hazard ratios of 0.86 (95% CI, 0.64-1.17), 0.62 (95% CI, 0.33-1.16), 3.24 (95% CI, 0.65-16.1), and 0.45 (95% CI, 0.24-0.87). Height loss was reduced by calcium in the per-protocol population (P=.03). Serum alkaline phosphatase and procollagen type-I N-terminal propeptide were lower in the calcium group at 5 years, but constipation was more common. CONCLUSIONS: Calcium results in a sustained reduction in bone loss and turnover, but its effect on fracture remains uncertain. Poor long-term compliance limits its effectiveness.
Maturitas. 2006 Aug 26; [Epub ahead of print]
High-dose testosterone is associated with atherosclerosis in postmenopausal women.
Hak AE, Westendorp IC, Pols HA, Hofman A, Witteman JC.
Department of Epidemiology & Biostatistics, Erasmus Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
OBJECTIVES: To study the long-term effects of androgen treatment on atherosclerosis in postmenopausal women. METHODS: In a population-based study in 513 naturally postmenopausal women aged 54-67 years, we studied the association between self-reported intramuscularly administered high-dose estrogen-testosterone therapy (estradiol- and testosterone esters) and aortic atherosclerosis. Aortic atherosclerosis was diagnosed by radiographic detection of calcified deposits in the abdominal aorta, which have been shown to reflect intima atherosclerosis. Hormone therapy users were compared with never users. RESULTS: Intramuscular hormone therapy use for 1 year or longer was reported by 25 women. In almost half of these women severe atherosclerosis of the aorta was present (n=11), while in women without hormone use severe atherosclerosis of the aorta was present in less than 20% (OR 3.1; 95% CI, 1.1-8.5, adjusted for age, years since menopause, smoking, and body mass index). The association remained after additional adjustment for diabetes, cholesterol level, systolic blood pressure, or alcohol use. No association was found for hormone use less than 1 year. CONCLUSION: Our results suggest that high-dose testosterone therapy may adversely affect atherosclerosis in postmenopausal women and indicate that androgen replacement in these women may not be harmless.
Arq Bras Endocrinol Metabol. 2006 Jun;50(3):505-14
Effects of transdermic estrogen therapy, isolated or in association with micronized progesterone, on clotting factors in overweight or normal postmenopausal women
de Farias M, Cruz L, Clapauch R, Siqueira C.
Setor de Hematologia, Setor de Endocrinologia, Servico de Clinica Medica, Hospital da Lagoa, Rio de Janeiro, RJ.
To evaluate HRT action over hemostasis we treated 45 postmenopausal women, divided in: Group 1 (N= 22, hysterectomized) and Group 2 (N= 23, with uterus), at the average age of 51.6 years and average BMI of 27.1 kg/m(2), with no significant difference in the base-line, with 17beta-oestradiol, 50 mcg/day, transdermic and continuous (group 1) associated to micronized progesterone 200 mg 12 days per month (group 2). The average of 2 samples of TAP, PTT, fibrinogen and platelet number was measured monthly during 3 months. For the total sample, there was a PTT shortening along treatment, from the second evaluation on (p= 0.006). Fibrinogen in Group 2 was significantly higher than in Group 1, from the second evaluation on (p= 0.0005). Patients with BMI > 25 presented a greater TAP shortening (p= 0.040) and a smaller fibrinogen drop (p= 0.033) than patients with BMI < 25. Prothrombotic effects predominated, especially in overweight women and in those who used progesterone.
Arq Bras Endocrinol Metabol. 2006 Jun;50(3):456-65
Prevalence of metabolic syndrome in a semi-arid rural area in Bahia
de Oliveira EP, de Souza ML, de Lima MD.
Faculdade de Farmacia, Universidade Federal da Bahia, Salvador, BA. epo@ufba.br
The goal of this study was to determine the prevalence of Metabolic Syndrome (MS) in a semi-arid rural area in Bahia, motivated by the increase of impaired glucose tolerance in rural populations and the scant national data about the occurrence of MS. Total sample involved 240 adults > or = 25 years, randomly selected, 102 (42.5%) men and 138 (57.5%) women, mean age 49.5 +/- 14.9, ranging from 25 to 87 years. Diagnosis was based on the I Diretriz Brasileira de Diagnostico e Tratamento da SM. Crude prevalence was 30.0% while the age-adjusted prevalence was 24.8%. MS frequency was higher in women (38.4%) than in men (18.6%), more elevated among individuals with age > or = 45 years (41.4%) than among those with age < 45 years (15.9%). Stratification performed according to sex and age revealed higher prevalence among women > or = 45 years (56.9%), probably associated to menopause. Presence of MS in the absence of impaired fasting glycemia and obesity, namely its best-established constituents, suggests the importance of the syndromic diagnosis, indicated by the high predictive value of some isolated metabolic alterations. High prevalence of MS requires attention for the treatment of the whole syndrome, retarding or preventing future consequences, like diabetes and cardiovascular disease.
N Engl J Med. 2006 Aug 24;355(8):763-78. Epub 2006 Aug 22
Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old.
Adams KF, Schatzkin A, Harris TB, Kipnis V, Mouw T, Ballard-Barbash R, Hollenbeck A, Leitzmann MF.
Nutritional Epidemiology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md, USA. adamske@mail.nih.gov
BACKGROUND: Obesity, defined by a body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters) of 30.0 or more, is associated with an increased risk of death, but the relation between overweight (a BMI of 25.0 to 29.9) and the risk of death has been questioned. METHODS: We prospectively examined BMI in relation to the risk of death from any cause in 527,265 U.S. men and women in the National Institutes of Health-AARP cohort who were 50 to 71 years old at enrollment in 1995-1996. BMI was calculated from self-reported weight and height. Relative risks and 95 percent confidence intervals were adjusted for age, race or ethnic group, level of education, smoking status, physical activity, and alcohol intake. We also conducted alternative analyses to address potential biases related to preexisting chronic disease and smoking status. RESULTS: During a maximum follow-up of 10 years through 2005, 61,317 participants (42,173 men and 19,144 women) died. Initial analyses showed an increased risk of death for the highest and lowest categories of BMI among both men and women, in all racial or ethnic groups, and at all ages. When the analysis was restricted to healthy people who had never smoked, the risk of death was associated with both overweight and obesity among men and women. In analyses of BMI during midlife (age of 50 years) among those who had never smoked, the associations became stronger, with the risk of death increasing by 20 to 40 percent among overweight persons and by two to at least three times among obese persons; the risk of death among underweight persons was attenuated. CONCLUSIONS: Excess body weight during midlife, including overweight, is associated with an increased risk of death.
Semana del 20 al 26 de Septiembre de 2006
Dr. Juan Enrique Blümel
Epilepsia. 2006 Sep;47(9):1447-51
Hormone replacement therapy in women with epilepsy: a randomized, double-blind, placebo-controlled study.
Harden CL, Herzog AG, Nikolov BG, Koppel BS, Christos PJ, Fowler K, Labar DR, Hauser WA.
Comprehensive Epilepsy Center, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York, USA.
Purpose: Previous reports have suggested that hormone replacement therapy (HRT) could increase seizure activity in women with epilepsy. We sought to determine whether adding HRT to the medication regimen of postmenopausal women with epilepsy was associated with an increase in seizure frequency. Methods: This was a randomized, double-blind, placebo-controlled trial of the effect of HRT on seizure frequency in postmenopausal women with epilepsy, taking stable doses of antiepileptic drugs (AEDs), and within 10 years of their last menses. After a 3-month prospective baseline, subjects were randomized to placebo, Prempro (0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate or CEE/MPA) daily, or double-dose CEE/MPA daily for a 3-month treatment period. Results: Twenty-one subjects were randomized after completing baseline. The subjects' ages ranged from 45 to 62 years (mean, 53 years; SD, +/-5), and the number of AEDs used ranged from none to three (median, one). Five (71%) of seven subjects taking double-dose CEE/MPA had a worsening seizure frequency of at least one seizure type, compared with four (50%) of eight taking single-dose CEE/MPA and one (17%) of six taking placebo (p = 0.05). An increase in seizure frequency of the subject's most severe seizure type was associated with increasing CEE/MPA dose (p = 0.008). An increase in complex partial seizure frequency also was associated with increasing CEE/MPA dose (p = 0.05). Two subjects taking lamotrigine had a decrease in lamotrigine levels of 25-30% while taking CEE/MPA. Conclusions: CEE/MPA is associated with a dose-related increase in seizure frequency in postmenopausal women with epilepsy. CEE/MPA may decrease lamotrigine levels.
J Clin Endocrinol Metab. 2006 Sep 19; [Epub ahead of print]
Controversies Regarding Transdermal Androgen Therapy in Postmenopausal Women.
Basaria S, Dobs AS.
Department of Medicine, Division of Endocrinology & Metabolism, The Johns Hopkins University School .
Context: Recently, the field of androgen therapy in postmenopausal women has received much attention and press. Although the ovary ceases to produce follicles and estrogen at menopause, it continues to produce androgens. Hence, many oophorectomized women complain of sexual dysfunction (despite adequate estrogenization). Previous studies of non-transdermal testosterone replacement have shown an improvement in libido and sexual frequency, though at the cost of supraphysiological testosterone levels. Transdermal testosterone patch (Intrinsa((TM))) was developed to deliver physiological amount of testosterone. In 2004, the FDA voted not to approve Intrinsa((TM)) until long-term safety data are available. Evidence Acquisition: Recent trials of Intrinsa((TM)) in postmenopausal women were included. A MEDLINE search was conducted for articles published over the last 40 yr based on the key words androgen therapy/replacement and postmenopausal women. Relevant placebo-controlled trials of non-transdermal androgen therapy in postmenopausal women were also reviewed. Evidence Synthesis: Early results from industry-funded trials show that transdermal testosterone therapy results in only moderate (though statistically significant) improvement in libido in surgically menopausal women (on estrogen). However, the published data are of short duration (24 weeks). Hence, long-term safety in these women remains unclear. Conclusion: We recommend a short-term trial (not to exceed 24 weeks) of transdermal testosterone therapy (once approved) in surgically menopausal (estrogenized) women with distressful sexual dysfunction. Until the patch gets approval, a short trial of oral methyltestosterone in deserving estrogenized women may be justified.
Maturitas. 2006 Sep 20;55(2):174-9.
Risk factors for clinically diagnosed uterine fibroids in women around menopause.
Parazzini F.
Gruppo di Studio Progetto Menopausa Italia, AOGOI, Via Abamonti 1, Milano, Italy.
OBJECTIVE: We analysed the risk factors for clinically diagnosed uterine fibroids in women attending menopause clinics in Italy. METHODS: Between 1997 and 2003 we conducted a large cross-sectional study on the characteristics of women around menopause attending a network of first-level outpatient menopause clinics in Italy for general counselling about menopause or treatment of menopausal symptoms. A total of 85,967 non-hysterectomized women not reporting myomectomy entered the study; 2239 had a diagnosis of uterine fibroids. A woman was defined as having uterine fibroids if she had at gynecological examination an enlarged uterus (2 months of gestation or more) and a clinical diagnosis of fibroids. In 769 cases was performed in ultrasound examination which confirmed the diagnosis. RESULTS: In comparison with women with a body mass index (BMI) <22, the multivariate ORs for BMI 26 or more were 1.30 (95% CI, 1.09-1.55) for cases with clinical diagnosis, and 1.29 (95% CI, 1.01-1.45) for women with ultrasonographic diagnosis. In comparison with premenopausal women, the multivariate OR for clinically detected fibroids was 0.63 (95% CI, 0.55-0.72) for post-menopausal ones. The risk of fibroids was lower in parous women than in nulliparous ones, and the risk decreased with number of births regardless the type of diagnosis. CONCLUSION: This study confirms in a large sample that parity is the main protective factor for the development of fibroids. Overweight increases the risk.
Clin Endocrinol (Oxf). 2006 Oct;65(4):506-13
Sex-specific association of the androgen to oestrogen ratio with adipocytokine levels in older adults: the Rancho Bernardo Study.
Laughlin GA, Barrett-Connor E, May S.
Department of Family and Preventive Medicine, School of Medicine, University of California, San Diego.
Abstract Objective Androgens and oestrogens have opposing effects on some adipocyte functions. Thus, the androgen to oestrogen balance may be as important as the individual hormones in determining the biological interaction between endogenous sex hormones and adipocyte-derived factors such as adiponectin and leptin. We tested this hypothesis by evaluating the sex-specific, cross-sectional association of sex hormones and androgen to oestrogen ratios with serum adiponectin and leptin in older men and postmenopausal women. Design Cross-sectional. Participants A total of 1510 community dwelling men and postmenopausal women aged 50-92 years. Measurements Serum leptin, adiponectin and sex hormone levels. Results Adiponectin and leptin levels were higher in women than men (P < 0.001). In both sexes, adiponectin concentrations were lower, and leptin levels higher, with increasing BMI and waist girth (all P < 0.001). Although the ratio of total testosterone to total oestradiol was significantly associated with both adipocytokines in both sexes, the strongest and most consistent hormone-adipocytokine associations were observed when the androgen to oestrogen ratio was expressed as total testosterone to bioavailable oestradiol. In linear regressions, the testosterone to bioavailable oestradiol ratio was positively related to adiponectin and inversely related to leptin, with nearly identical standardized beta-coefficients for men and women (all P < 0.001). The strength of the hormone ratio-adipocytokine associations was reduced, but not eliminated, after adjustment for age, adiposity and cardiovascular disease risk factors, including insulin resistance. Conclusions The striking similarity of the hormone ratio-adipocytokine associations for men and women, despite wide differences in sex hormone and adipocytokine levels, suggests these results reflect underlying physiological mechanisms common to both sexes.
Reuters Health Information
Metformin Useful for Preventing Early Puberty in Girls With Precocious Pubarche
NEW YORK (Reuters Health) Sept 11 - Treatment with metformin can help delay the onset of puberty in girls with precocious pubarche, defined as pubic hair first appearing at younger than 8 years of age, new research suggests. Moreover, metformin therapy allows height gain to be maintained, the researchers report in the Journal of Clinical Endocrinology and Metabolism for August. Precocious pubarche has been identified as a risk factor for early onset and rapid progressively puberty, especially in the context of restrained prenatal growth, lead author Dr. Lourdes Ibanez, from the University of Barcelona in Spain, and colleagues note. Because this may relate to insulin resistance, treatment with the insulin sensitizing drug metformin might prove beneficial. To test this, the team studied 38 girls with precocious pubarche thought to stem from exaggerated adrenarche. The subjects were randomized to receive metformin (425 mg/day) or no treatment for 2 years. Metformin therapy was associated with a drop in body adipose composition and serum leptin levels. In addition, this therapy appeared to delay the clinical onset of puberty (Tanner breast stage 2) by 0.4 year. Further analysis supported the puberty-delaying effects of metformin by showing that the puberty-associated rise in insulin-like growth factor-I was delayed by at least 1 year. Moreover, treatment with the drug also seemed to delay the onset of menarche. Despite the slower pubertal transition, girls on metformin maintained gains in height and lean mass. "The efficacy of metformin treatment in precocious pubarche girls is extended to include not only a less adipose body composition after 2 years but also a less advanced onset of puberty and menses, while height gain is maintained," the researchers concluye
Endocrinology. 2006 Sep 21; [Epub ahead of print]
Regulation of AMPK and Lipogenesis by Androgens Contributes to Visceral Obesity in an Estrogen Deficient State.
McInnes KJ, Corbould A, Simpson ER, Jones ME.
Prince Henry's Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
Menopause is associated with an accumulation of visceral fat. An emerging concept suggests that relatively elevated levels of circulating androgens compared with estrogens in post-menopausal women underlie this shift in body-fat distribution. In this study we administered dihydrotestosterone (DHT) to ovariectomised (ovx) mice to examine the effect of relative androgen excess on adipose tissue distribution and function in estrogen-deficient mice. Compared with controls, DHT-treated mice exhibited increased body weight and visceral fat mass associated with triglyceride accumulation. Phosphorylation of AMP-activated-protein-kinase (AMPK) and Acetyl-CoA-Carboxylase (ACC) was significantly decreased by DHT in visceral fat. In 3T3-L1 cells, DHT decreased phosphorylation of AMPK in a dose-dependent manner. In addition, DHT increased the expression of lipogenic genes (Fatty-Acid-Synthase, Sterol Regulatory Element Binding Protein-2 and Lipoprotein Lipase) in visceral fat. These data provide the first in vivo evidence that an increased androgen-estrogen ratio can promote visceral fat accumulation by inhibiting AMPK activation and stimulating lipogenesis.
Rev Urol. 2001;3 Suppl 1:S2-6
The prevalence of urinary incontinence.
Nitti VW.
Urinary incontinence is a significant health problem with considerable social and economic impact. It is important to distinguish between prevalence and incidence with regard to incontinence, and prevalence-the probability of having incontinence within a defined population at a defined point in time-is the more important when considering its impact and the utilization of healthcare resources. There are large variations in the severity and impact of incontinence, and its severity, frequency, and predictability all need to be considered when evaluating its effects on patients, The degree of bother is particularly significant when determining who will need treatment. Incontinence may be a result of bladder dysfunction, sphincter dysfunction, or a combination of both, but large-scale studies are not designed to determine the etiology. In young women, the prevalence of incontinence is usually low, but prevalence peaks around menopause, with a steady rise there-after into later life. Although the prevalence of stress and mixed (stress and urge) incontinence is higher than urge incontinence, the latter is more likely to require treatment. In women, moderate and severe bother have a prevalence ranging from about 3% to 17%. Severe incontinence has a low prevalence in young women, but rapidly increases at ages 70 through 80. In men, the prevalence of incontinence is much lower than in women, about 3% to 11% overall, with urge incontinence accounting for 40% to 80% of all male patients. Stress incontinence accounts for less than 10% of cases and is attributable to prostate surgery, trauma, or neurological injury. Incontinence in men also increases with age, but severe incontinence in 70- to 80-year-old men is about half of that in women. The most effective therapy for incontinence will rely on targeting the correct populations to be treated, which depends on how data is collected on prevalence and severity.
Expert Opin Biol Ther. 2006 Oct;6(10):1041-1050
RANK ligand inhibition with denosumab for the management of osteoporosis
Lewiecki EM.
New Mexico Clinical Research & Osteoporosis Center, Albuquerque, New Mexico 87106, USA.
Receptor activator of nuclear factor-kappaB ligand (RANKL) is a cytokine member of the tumour necrosis factor family that is the principal final mediator of osteoclastic bone resorption. It plays a major role in the pathogenesis of postmenopausal osteoporosis, as well bone loss associated with rheumatoid arthritis, metastatic cancer, multiple myeloma, aromatase inhibitor therapy and androgen deprivation therapy. Denosumab (AMG 162) is an investigational fully human monoclonal antibody with a high affinity and specificity for RANKL. By inhibiting the action of RANKL, denosumab reduces the differentiation, activity and survival of osteoclasts, thereby slowing the rate of bone resorption. Denosumab has been shown to increase bone mineral density (BMD) and reduce bone turnover in postmenopausal women with low BMD. Denosumab is a potential treatment for osteoporosis and other skeletal disorders.
JAMA. 2006 Sep 12; [Epub ahead of print]
Cardiovascular Risk and Inhibition of Cyclooxygenase: A Systematic Review of the Observational Studies of Selective and Nonselective Inhibitors of Cyclooxygenase 2.
McGettigan P, Henry D.
Discipline of Clinical Pharmacology, School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia.
CONTEXT: Evidence that rofecoxib increases the risk of myocardial infarction has led to scrutiny of other nonsteroidal anti-inflammatory drugs (NSAIDs). Regulatory agencies have provided variable advice regarding the cardiovascular risks with older nonselective NSAIDs. OBJECTIVE: To undertake a systematic review and meta-analysis of controlled observational studies to compare the risks of serious cardiovascular events with individual NSAIDs and cyclooxygenase 2 inhibitors. DATA SOURCES: Searches were conducted of electronic databases (1985-2006), scientific meeting proceedings, epidemiological research Web sites, and bibliographies of eligible studies. STUDY SELECTION: Eligible studies were of case-control or cohort design, reported on cardiovascular events (predominantly myocardial infarction) with cyclooxygenase 2 inhibitor, NSAID use, or both with nonuse/remote use of the drugs as the reference exposure. Of 7086 potentially eligible titles, 17 case-control and 6 cohort studies were included. Thirteen studies reported on cyclooxygenase 2 inhibitors, 23 on NSAIDs, and 13 on both groups of drugs. DATA EXTRACTION: Two people independently extracted data and assessed study quality with disagreements resolved by consensus. DATA SYNTHESIS: Data were combined using a random-effects model. A dose-related risk was evident with rofecoxib, summary relative risk with 25 mg/d or less, 1.33 (95% confidence interval [CI], 1.00-1.79) and 2.19 (95% CI, 1.64-2.91) with more than 25 mg/d. The risk was elevated during the first month of treatment. Celecoxib was not associated with an elevated risk of vascular occlusion, summary relative risk 1.06 (95% CI, 0.91-1.23). Among older nonselective drugs, diclofenac had the highest risk with a summary relative risk of 1.40 (95% CI, 1.16-1.70). The other drugs had summary relative risks close to 1: naproxen, 0.97 (95% CI, 0.87-1.07); piroxicam, 1.06 (95% CI, 0.70-1.59); and ibuprofen, 1.07 (95% CI, 0.97-1.18). CONCLUSIONS: This review confirms the findings from randomized trials regarding the risk of cardiovascular events with rofecoxib and suggests that celecoxib in commonly used doses may not increase the risk, contradicts claims of a protective effect of naproxen, and raises serious questions about the safety of diclofenac, an older drug.
Semana del 13 al 19 de Septiembre de 2006
Dr. Juan Enrique Blümel
(Enviado por Luis Danckers)
Recomendaciones 2006 de la Nams para el manejo de la Osteoporosis en la Mujer Postmenopaúsica
Las estrategias de manejo para la osteoporosis en las mujeres posmenopáusicas requieren la evaluación de factores de riesgo para `osteoporosis` y para fractura osteoporótica, definida esta por la densidad mineral ósea (BMD). Una vez realizado esto se deben instituir medidas para reducir estos factores de riesgo mediante los cambios del modo de vida y eventualmente, si esta indicada, terapia farmacológica. Debe alentarse en todas las mujeres posmenopáusicas que empleen prácticas de modo de vida que reducen el riesgo del escape óseo y de fracturas osteoporóticas: manteniendo un peso saludable, comer un régimen alimentario equilibrado, obteniendo calcio y la vitamina D adecuada, realizar ejercicio apropiado, evitar el consumo de alcohol excesivo, no fumando y usando las medidas para prevenir las caídas. Los exámenes periódicos del calcio, la ingesta de vitamina D y los comportamientos del modo de vida son útiles. Después de la menopausia, el riesgo de caídas de una mujer debe evaluarse al menos anualmente. La exploración física debe incluir una medición anual de la talla y el peso, junto con una evaluación para la cifosis y el dolor lumbar.
El estudio de la BMD (densidad mineral ósea) se indica para:
" Todas las mujeres posmenopáusicas con causas médicas del escape óseo
" Todas las mujeres posmenopáusicas de 65 años o más de edad.
" Mujeres posmenopáusicas saludables menores de la edad 65 que tienen uno o más de los siguiente factores de riesgo:
" Antecedentes de fracturas (hueso facial, tobillo, dedo de la mano, dedo del pie, etc) después de la menopausia
" Delgadez [peso corporal <127 lb (57,7 kg) o IMC kg/m <212]
" Antecedentes de la fractura de la cadera en un progenitor
" Fumadora actual
Cuando el estudio de la BMD la DXA es la técnica preferida. La cadera total, el cuello femoral y la espina dorsal lumbar postero-anterior deben medirse, usando el más bajo de las tres puntuaciones de BMD. El uso corriente de los marcadores bioquímicos del recambio óseo en la práctica clínica no se recomienda en general.
Si la osteoporosis se diagnostica clínicamente o por BMD, debe investigarse cualquier causa secundaria, aunque la evidencia que define el examen más minucioso o eficaz en función de los costos es limitada. La fractura vertebral debe confirmarse, mediante o una evaluación de fracturas vertebrales con medición de DXA de la espina dorsal o ante el hallazgo en la radiografía espinal de una pérdida de altura de más de 20% (o 4 mm). En las mujeres posmenopáusicas, la necesidad de prescribir terapia de osteoporosis se basa en una combinación de la BMD y los factores de riesgo. La farmacoterapia `de osteoporosis` se recomienda en las siguientes poblaciones:
" Todas las mujeres posmenopáusicas que han tenido una fractura vertebral osteoporótica
" Todas las mujeres posmenopáusicas que tienen valores de BMD compatibles con osteoporosis (es decir, T-puntuación peor que o igual a--2,5)
" Todas las mujeres posmenopáusicas que tienen una T-puntuación de -2,0 a -2,5 más al menos uno de los siguiente factores de riesgo de fractura: la delgadez, los antecedentes de la fractura de fragilidad luego de la menopausia (hueso facial, tobillo, dedo de la mano, dedo del pie, etc) y los antecedentes de la fractura de la cadera en un progenitor.
Las recomendaciones de tratamientos se basan en datos de eficacia y datos clínicos, que incluyen: magnitud del riesgo de fracturas, el perfil del efecto colateral, la tolerancia de drogas específicas, los riesgos extraesqueléticos, los beneficios potenciales, las enfermedades de confusión, el costo y la preferencia de pacientes, incluida la elección de la dosificación. La selección de una terapia sobre otra no puede hacerse sobre la base de las pruebas clínicas, porque no se han realizado los ensayos cara a cara que comparan la efectividad de las terapias farmacológicas para reducir el riesgo de fracturas.
1. Los bisfosfonatos son las drogas de primera línea para tratar a las mujeres posmenopáusicas con osteoporosis. El alendronato y risedronato reducen el riesgo de las fracturas tanto vertebrales como no vertebrales. Si hay diferencias en la protección de fracturas entre los bisfosfonatos, esto es incierto. Es probable que todos los productos produzcan una mayor reducción del riesgo de fracturas en las mujeres con osteoporosis más grave.
2. El raloxifeno es el SERM con mayor frecuencia se considera en el tratamiento las mujeres posmenopáusicas con masa ósea baja o en mujeres posmenopáusicas más jóvenes con osteoporosis que están en riesgo mayor de la fractura de la espina dorsal que de fractura de la cadera. Previene el escape óseo y reduce el riesgo de las fracturas vertebrales, pero su efectividad al reducir otras fracturas es incierto. Los riesgos extraesqueléticos y los beneficios son importantes al considerar la terapia de raloxifeno.
3. El teriparatide (PTH 1-34) se reserva para tratar a las mujeres en alto riesgo de la fractura, incluido aquellos con BMD muy bajo (T-puntuación peor que -3,0) con una fractura vertebral anterior. PTH mejora a BMD y reduce el riesgo de las fracturas nuevas vertebrales y no vertebrales. Los requisitos de administración (inyecciones subcutáneas es decir, diarias) pueden limitar el uso.
4. La indicación primaria para estrogenoterapia sistémica (Estrógenos solos o con progesterona) es tratar los síntomas moderados y graves de menopausia (síntomas vasomotores). Cuando los síntomas se controlan o cesan, la terapia con hormonas todavía puede considerarse para los efectos óseos, sopesando sus beneficios y los riesgos contra los de las terapias alternativas.
5. La calcitonina no es una droga de primera línea para el tratamiento de osteoporosis posmenopáusica, debido a que su eficacia para prevenir las fracturas no es importante y sus efectos de BMD son menos que los de otros agentes. Sin embargo, es una opción para las mujeres con osteoporosis que cursan más de 5 años de la menopausia. La terapia de calcitonina puede reducir el riesgo de fracturas vertebrales en las mujeres con osteoporosis, aunque la evidencia que documenta la protección de fracturas no es fuerte. No se recomienda para tratar el dolor óseo, excepto el dolor óseo de las fracturas vertebrales agudas de compresión.
6. Los datos son inadecuados a hacer las recomendaciones definitivas con respecto a la combinación o la farmacoterapia seriada anti-reabsorbente y anabólica.
Durante la terapia, es importante evaluar en forma continua el resultado de los tratamientos y de la elección de la medicación mediante el examen médico periódico y la medición de la BMD. La medición de BMD tiene un uso limitado en la predicción de la efectividad de las terapias antireabsorbentes para reducir el riesgo de fracturas. Además, reducciones de riesgos de fracturas de la terapia ocurren mucho más rápidamente que los cambios de densidad ósea. Un intervalo apropiado para BMD repetido ensayo es 2 años. Es importante promover la adherencia al plan de tratamiento y ayudar a identificar las barreras a la no adherencia. El Proveer información clara a las mujeres con respecto a su riesgo de la fractura y la finalidad de la terapia de osteoporosis puede ser la manera óptima para mejorar la adherencia. Si ocurren efectos adversos relacionados con medicamentos, deben instituirse las estrategias apropiadas de manejo. Si persisten los efectos adversos puede estar indicado el cambio a otro agente. El tratamiento de la osteoporosis` de ser a largo plazo en la mayoría de las mujeres. Las decisiones para descontinuar o suspender la terapia se deben basar en el riesgo de fractura y su respuesta al tratamiento, como así como la probabilidad de que el efecto beneficioso del agente usado se reduzca con el tiempo. Dadas las incertidumbres en la seguridad a largo plazo, se requiere vigilancia cuidadosa. El riesgo de fracturas después de descontinuar la terapia no se ha evaluado adecuadamente.
Maturitas. 2006 Sep 6; [Epub ahead of print]
Differential effects of progestogens, by type and regimen, on estrogen-metabolizing enzymes in human breast cancer cells.
Xu B, Kitawaki J, Koshiba H, Ishihara H, Kiyomizu M, Teramoto M, Kitaoka Y, Honjo H.
Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
OBJECTIVES: To investigate the in vitro effects of five progestogens commonly used in hormone replacement therapy (HRT) on estrogen-metabolizing enzymes in human breast cancer cells. METHODS: The human hormone-dependent breast cancer cell lines T47D, MCF-7, and MCF-7aro were cultured with estradiol (E(2)) and progestogens. The mRNA levels of estrogen-metabolizing enzymes were determined by RT-PCR or Northern blot, and enzyme activities by radiolabeled substrates. Cell proliferation was measured by bromodeoxyuridine incorporation. In vitro models for continuous combined regimen (CCR) and sequential combined regimen (SCR) were established to mimic the in vivo conditions of HRT. RESULTS: Medroxyprogesterone acetate (MPA) plus E(2) (10(-8)M) stimulated the mRNA levels and activities of estrogen-activating enzymes aromatase (at 10(-8)M MPA), 17beta-hydroxysteroid dehydrogenase type 1 (17betaHSD1) (at 10(-6)M), and sulfatase (at 10(-8) to 10(-6)M) compared to E(2) only. Progesterone also stimulated enzyme activity, but to a lower magnitude. Levonorgestrel, norethindrone, and dienogest showed no enzyme stimulation. The estrogen-inactivating enzymes 17beta-hydroxysteroid dehydrogenase type 2 and sulfotransferase were not affected by any of the progestogens tested. However, all the progestogens (at 10(-8) to 10(-6)M) inhibited E(2)-stimulated cell proliferation. While increased aromatase and 17betaHSD1 activities were observed in the CCR model, no significant enzyme stimulation was observed in the SCR model. CONCLUSIONS: The present study suggested that progestogens exert different actions on estrogen-metabolizing enzymes in breast cancer cells dependent on the specific progestogen and regimen used. Further studies are needed to elucidate whether MPA, a progestogen currently used in HRT, leads to a higher risk of breast cancer development than other progestogens.
Menopause. 2006 Sep 12; [Epub ahead of print]
Oxidative stress explains differences in large elastic artery compliance between sedentary and habitually exercising postmenopausal women.
Moreau KL, Gavin KM, Plum AE, Seals DR.
From the 1Department of Integrative Physiology, University of Colorado at Boulder, Boulder, CO; and 2Division of Geriatric Medicine, Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, CO.
OBJECTIVE:: To determine whether oxidative stress contributes to differences in large elastic artery compliance between sedentary and habitually exercising postmenopausal women. DESIGN:: Carotid artery compliance was measured during acute intravenous infusions of saline (control) and supraphysiological doses of the potent antioxidant ascorbic acid (vitamin C) in sedentary (n = 15; 58 +/- 1 years) and endurance exercise-trained (n = 11, 59 +/- 1) healthy postmenopausal women. RESULTS:: Carotid artery compliance was 24% higher in the exercising versus sedentary women during control (P < 0.001). During ascorbic acid infusion, carotid artery compliance was increased by 28% in the sedentary women (1.29 +/- 0.12 to 1.60 +/- 0.12 mm/mm Hg x 10, P < 0.001 vs control) but was unchanged in exercising women (1.60 +/- 0.14 vs 1.48 +/- 0.14 mm/mm Hg x 10, P = 0.10), abolishing the habitual exercise-associated baseline difference. The change in compliance with ascorbic acid was most strongly related to maximal aerobic capacity (r = -0.64, P < 0.0001) and body fatness (r = 0.60, P < 0.0001) and was more modestly related to oxidized low-density lipoprotein, waist circumference, interleukin-6, total and low-density lipoprotein cholesterol (all r = 0.40 to 0.49, all P < 0.05), and high-density lipoprotein cholesterol (r = -0.48, P = 0.01). Carotid artery diameter, blood pressure, and heart rate were unaffected by ascorbic acid. CONCLUSIONS:: These results indicate that the greater large elastic artery compliance in habitually exercising compared with sedentary estrogen-deficient postmenopausal women may be mediated by an absence of oxidative stress, perhaps related in part to more favorable cardiovascular risk factors.
Arterioscler Thromb Vasc Biol. 2006 Sep 14; [Epub ahead of print]
Conjugated Equine Estrogen, Esterified Estrogen, Prothrombotic Variants, and the Risk of Venous Thrombosis in Postmenopausal Women.
Smith NL, Heckbert SR, Lemaitre RN, Reiner AP, Lumley T, Rosendaal FR, Psaty BM.
Department of Epidemiology, Medicine, Biostatistics, and Health Services, University of Washington, Seattle; and the Department of Clinical Epidemiology and Hematology, Leiden University Medical Center, Leiden, the Netherlands.
Background--Joint exposure to oral conjugated equine estrogen (CEE) and prothrombotic genetic variants factor II G20210A or factor V G1601A (Leiden) increase venous thrombotic risk 6- to 16-fold in postmenopausal women. Esterified estrogen (EE), an alternative estrogenic compound, appears not to be associated with increased risk and nothing is known about the joint risk with prothrombotic genetic variants. METHODS AND RESULTS: We conducted a population-based, case-control study among postmenopausal women within a health maintenance organization. Subjects included 328 cases who sustained a first venous thrombosis and 1591 controls. Current hormone use was defined using electronic pharmacy records and variants FII G20210A and FV Leiden were genotyped using blood samples. FII and FV Leiden variants were associated with 2.1-fold and 3.7-fold increases in venous thrombotic risk, respectively. Overall, CEE use was associated with a 2.5-fold increase in risk compared with no hormone use, whereas EE use was not associated with a statistically increased risk. Compared with no hormone use and no variant, joint exposure to CEE and either prothrombotic variant was associated with an odds ratio (OR) of 9.1 (95% CI: 4.5 to 18.2), whereas joint exposure to EE and either variant was associated with an OR of 2.1 (0.6 to 6.8). When analyses were restricted to hormone users with either variant, CEE use was associated with an OR of 5.3 (1.3 to 21.7) compared with EE use. CONCLUSIONS: These findings need replication and suggest EE use is associated with less risk than CEE use especially among 5% to 10% of women who are carriers of a prothrombotic variant.
Rev Fac Cien Med Univ Nac Cordoba. 2005;62(2 Suppl 1):32-6
Current status of the hormone therapy during the menopausal transition and post-menopausa
Figueroa-Casas PR.
Universidad Nacional de Rosario.
Starting from prospective clinical studies that have evaluated its benefits and risks, hormone replacement therapy in menopause women has been reassessed in its indications in the last four years. In October, 2004 a Latinamerican Experts Consensus was carried out, such report with some modifications is presented in this publication. The conclusions the experts reached were the following: 1) Hormone Therapy is the gold standard for the control of moderate to severe vasomotor symptoms; 2) this therapy must be indicated in an individual manner and only in symptomatic women in which the benefit is greater than the risk; 3) the least effective dose must be used; 4) it must be used neither for cardiovascular prevention, osteoporosis, colon cancer nor for mental disorder; 5) the patient must be informed about the benefits and risks.
Ginecol Obstet Mex. 2006 Jun;74(6):312-6
Symptomatic profile in peri and postmenopausal women
Horna Lopez A, Romero Gutierrez G, Horna Quiroz M, Malacara Hernandez JM, Perez Luque EL.
Medica pasante del servicio social en investigacion, Hospital de Ginecopediatria numero 48, Leon, Guanajuato.
OBJECTIVE: To determine the symptoms that women refer during peri and postmenopause. PATIENTS AND METHOD: A cross-sectional study was carried out from April to December 2005; 500 women between 45 and 65 years old were included. We applied them the NR 1 questionnaire of symptoms for mature women. Data were obtained by means of a face-to-face interview. Results were analyzed through descriptive statistics, with percentage values, arithmetic mean and standard deviation. Differences between groups were evaluated with Student's T test, chi square test, and Fisher exact test. RESULTS: Perimenopausal women had higher levels of depression (p = 0.03). Postmenopausal women presented higher frequency of sleep disturbances (p = 0.003). We found that perimenopausal women had more night sweats (p = 0.005), excessive hot (p = 0.006), hot flashes (p = 0.001), headaches (p = 0.001), vaginal dryness (p = 0.03), and dyspareunia (p = 0.005). On the other hand, postmenopausal women presented higher frequency of changes in libido (p = 0.001). CONCLUSIONS: In general, perimenopausal women have more symptoms than posmenopausal women. It is advisable an exhaustive analysis of the perimenopausal women symptoms in order to offer them an integral substitutive treatment.
Pharmacol Rev. 2006 Sep;58(3):389-462
The endocannabinoid system as an emerging target of pharmacotherapy.
Pacher P, Batkai S, Kunos G.
National Institutes of Health, NIAAA, Laboratory of Physiological Studies, 5625 Fishers Lane, Room 2S-24, Bethesda, MD 20892-9413. gkunos@mail.nih.gov.
The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson's and Huntington's disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB(1) receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB(1) receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB(2) receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients' need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.
Curr Med Res Opin. 2006 Sep;22(9):1757-64
Persistent bisphosphonate use and the risk of osteoporotic fractures in clinical practice: a database analysis study.
van den Boogaard CH, Breekveldt-Postma NS, Borggreve SE, Goettsch WG, Herings RM.
PHARMO Institute, Utrecht, The Netherlands.
INTRODUCTION: International guidelines on the treatment and prevention of osteoporosis recommend the use of bisphosphonates to prevent fractures in this population. However, low persistent use of bisphosphonates could considerably limit the prevention of fractures in clinical practice.OBJECTIVE: This study aimed to investigate the association between persistent use of bisphosphonates and the risk of osteoporotic fractures in clinical practice.METHODS: Data were obtained from the PHARMO Record Linkage System, which includes, among other databases, drug-dispensing records from community pharmacies linked to hospital discharge records of more than two million subjects in defined areas in the Netherlands. Persistence with bisphosphonate therapy was assessed during a period of 3 years. A nested matched case control study (cases:controls = 1:10) was performed to study the association between persistent bisphosphonate use and hospitalisation for osteoporotic fractures and analysed by conditional logistic regression analysis. The analyses were adjusted for patient characteristics such as previous hospitalisations for fractures, co-morbidity and co-medication.RESULTS: 14 760 new female users of bisphosphonates were identified of which 541 women had a hospitalisation for osteoporotic fracture after start of bisphosphonate treatment (1-3 years follow-up). One-year persistence rates increased from 33% with alendronate daily to 48% with alendronate weekly, an increase of 15%. Similar results were obtained with risedronate daily and weekly. One year persistent use of bisphosphonates resulted in a statistical significant 26% lower fracture rate (OR 0.74; 95%CI 0.57-0.95) whereas 2 year persistent use resulted in a 32% lower rate (OR 0.68; 95%CI 0.47-0.96).CONCLUSIONS: Persistent use of bisphosphonates decreases the risk of osteoporotic fractures in clinical practice. Approximately 6% of fractures among users of bisphosphonates could be prevented if persistence was improved by 20%. However, current persistence with bisphosphonate therapy is suboptimal and strategies that further increase persistence are likely to further prevent the number of fractures.
Rev Assoc Med Bras. 2006 Jul-Aug;52(4):256-60
Factors related to frequency of sexual activity of postmenopausal women.
De Lorenzi DR, Saciloto B.
Medicina da Universidade de Caxias do Sul, Caxias do Sul, RS.
OBJECTIVE: To identify factors related to the frequency of sexual activity of postmenopausal women METHODS: A cross-section study of 206 postmenopausal women between 45 and 60 years of age was made at a university health care service in the South of Brazil between June and October 2002. Evaluations were made of sexual activity according to the number of sexual intercourses in the previous month and the climacteric symptoms using the Kupperman index. Statistical analysis was performed with multiple linear regression analysis. RESULTS: Of those surveyed 176 (85%) women were sexually active. Although 60.6% reported a decrease in sexual activity after menopause, mostly attributing it to the husband's sexual impotence (41.7%). Approximately 25.7% stated they had no satisfaction with sexual intercourse. By means of multiple linear regression analysis the following aspects were associated to sexual activity: age (p<0.1), degree of sexual satisfaction (p=0.01), and climacteric symptomatology (p=0.02). As age increased the climacteric symptoms were more intense and sexual activity was less frequent with lower sexual satisfaction. The climacteric symptoms correlated with sexual activity were: hot flashes (p=0.05), irritability (p=0.04), melancholy/sadness (p=0.04), arthralgia/myalgia (p<0.01) and weakness/tiredness (p<0.01). CONCLUSION: Findings of this study were similar to those in literature. They agree with the hypothesis that sexuality of climacteric women is not only influenced by factors related to hypoestrogenism, but also by psychosocial and cultural aspects associated with aging itself. Nevertheless, longitudinal studies are necessary to provide more conclusive data. Special attention should be given to the sexual dysfunction of men.
J Steroid Biochem Mol Biol. 2006 Sep 9; [Epub ahead of print]
Isoflavone metabolites and their in vitro dual functions: They can act as an estrogenic agonist or antagonist depending on the estrogen concentration.
Hwang CS, Kwak HS, Lim HJ, Lee SH, Kang YS, Choe TB, Hur HG, Han KO.
Division of Endocrinology, Department of Internal Medicine, Cheil General Hospital and Women's Healthcare Center, Sungkyunkwan University School of Medicine, 1-19 Choong Gu Mukjung-Dong, Seoul 100-380, Republic of Korea; Department of Microbiological Engineering, Kon-kuk University, Seoul, Republic of Korea.
The major soy isoflavones are daidzin and genistin, the glycoside conjugates of daidzein (DZ) and genistein (GTN). After ingestion, they are metabolized into diverse compounds in the gut. The marked inter-individual variation has been suggested in their metabolism. The clinical effects may be modulated by the metabolic ability to produce a more potent metabolite than the precursor. Our study was, therefore, designed to analyze and compare in vitro biologic activities of their metabolites: DZ, GTN, dihydrogenistein (DGTN), dihydrodaidzein (DDZ), tetrahydrodaidzein (TDZ), O-desmethylangolensin (ODMA), and equol (EQL). Furthermore, we investigated their modulatory effects in the presence of estrogen using several in vitro systems. The intermediate metabolites, such as DGTN, DDZ, and TDZ, bind much weakly to both ERs and induce less potently in transcriptional activity, gene expression, and mammary cell proliferation than their precursors. EQL has the strongest binding affinities and estrogenic activities especially for ERbeta among the daidzin metabolites and shows the ability to suppress osteoclast formation at high doses. The test isoflavonoids act like estrogen antagonists with the premenopausal dose of E(2) and thus inhibit estrogenic actions by E(2), whereas they exert estrogen agonist activity with the lower dose of estrogen close to the serum levels of postmenopausal women. Our results suggest that phytoestrogens such as isoflavones may exert their effects as estrogen antagonists in a high estrogen environment, or they may act as estrogen agonists in a low estrogen environment.
BMC Womens Health. 2006 Sep 12;6(1):13 [Epub ahead of print]
Breast Cancer Risk associated with different HRT formulations: A register-based case-control study.
Dinger JC, Heinemann LA, Moehner S, Thai DM, Assmann A.
ABSTRACT: BACKGROUND: Previous epidemiological studies have inconsistently shown a modestly increased breast cancer risk associated with hormone replacement therapy (HRT). Limited information is available about different formulations - particularly concerning different progestins. METHODS: A case-control study was performed within Germany in collaboration with regional cancer registries and tumor centers. Up to 5 controls were matched breast cancer cases. Conditional logistic regression analysis was applied to estimate crude and adjusted odds ratios (OR) and 95% confidence intervals (95% CI). Stratified analyses were performed to compare the risk of different estrogens, progestins, and combinations. RESULTS: A total of 3593 cases of breast cancer were identified and compared with 9098 controls. The adjusted overall risk estimate for breast cancer (BC) associated with current or past use of HRT was 1.2 (1.1-1.3), and almost identical for lag times from 6 months to 6 years prior to diagnosis. No significant trend of increasing BC risk was found with increasing duration of HRT use, or time since first or last use in aggregate. Many established BC risk factors significantly modified the effect of HRT on BC risk, particularly first-degree family history of BC, higher age, lower education, higher body mass index (BMI), and never having used oral contraceptives (OCs) during lifetime. Whereas the overall risk estimates were stable, the numbers in many of the sub-analyses of HRT formulation groups (estrogens, progestins, and combinations) were too small for strong conclusions. Nevertheless, the BC risk seems not to vary much across HRT formulation subgroups. In particular, no substantial difference in BC risk was observed between HRT containing conjugated equine estrogens (CEE) or medroxyprogesterone acetate (MPA) and other formulations more common in Europe. CONCLUSIONS: The BC risk of HRT use is rather small. Low risk estimates for BC and a high potential for residual confounding and bias in this observational study do not permit causal conclusions. Apparently, there is not much variation of the BC risk across HRT formulations (estrogens, progestins). However, the small numbers and the overlapping nature of some of the subgroups suggest cautious interpretation.
