Semana del 29 de Noviembre al 5 de Diciembre de 2006

Dr. Juan Enrique Blümel

Obstet Gynecol. 2006 Dec;108(6):1354-60

Lyytinen H, Pukkala E, Ylikorkala O.

OBJECTIVE: To evaluate whether the risk of estrogen-only therapy on breast cancer varies by dose, constituent, and route of administration. METHODS: All Finnish women older than age 50 years using oral or transdermal estradiol (n=84,729), oral estriol (n=7,941), or vaginal estrogens (n=18,314) for at least 6 months during 1994-2001 were identified from the national medical reimbursement register. They were followed for breast cancer with the aid of the Finnish Cancer Registry to the end of 2002. RESULTS: Altogether, 2,171 women with breast cancer were identified. The standardized incidence ratio of breast cancer with systemic estradiol for less than 5 years was 0.93 (95% confidence interval 0.80-1.04), and for estradiol use for 5 years or more, 1.44 (1.29-1.59). Oral and transdermal estradiol was accompanied by a similar risk of breast cancer. The risk was most prominent with the dose greater than 1.9 mg/d orally; whereas the risk associated with transdermal route was not dose-dependent. The standardized incidence ratio for the lobular type of breast cancer (1.58) was slightly higher than that for the ductal type (1.36). The use of estradiol was associated with both localized breast cancer (1.45; 1.26-1.66) and cancer spread to regional nodes (1.35; 1.09-1.65). The incidence of carcinoma in situ (n=32) was increased (2.43; 1.66-3.42) among estradiol users. CONCLUSION: Estradiol for 5 years or more, either orally or transdermally, means 2-3 extra cases of breast cancer per 1,000 women who are followed for 10 years. Oral estradiol use for less than 5 years, oral estriol, or vaginal estrogens were not associated with a risk of breast cancer. LEVEL OF EVIDENCE: II-2.

Endocrinology. 2006 Nov 30; [Epub ahead of print]

Jover-Mengual T, Zukin RS, Etgen AM.

The importance of hormone therapy in affording protection against the sequelae of global ischemia in postmenopausal women remains controversial. Global ischemia arising during cardiac arrest or cardiac surgery causes highly selective, delayed death of hippocampal CA1 neurons. Exogenous estradiol ameliorates global ischemia-induced neuronal death and cognitive impairment in male and female rodents. However, the molecular mechanisms by which estrogens intervene in global ischemia-induced apoptotic cell death are unclear. Here we show that estradiol acts via the classical estrogen receptors, the IGF-I receptor and the ERK/MAPK signaling cascade to protect CA1 neurons in ovariectomized female rats and gerbils. We demonstrate that global ischemia promotes early dephosphorylation and inactivation of ERK1 and the transcription factor cAMP-response element binding protein (CREB), subsequent downregulation of the anti-apoptotic protein Bcl-2, a known gene target of estradiol and CREB, and activation of caspase-3. Estradiol treatment increases basal phosphorylation of both ERK1 and ERK2 in hippocampal CA1 and prevents ischemia-induced dephosphorylation and inactivation of ERK1 and CREB, downregulation of Bcl-2 and activation of the caspase death cascade. Whereas ERK/MAPK signaling is critical to CREB activation and neuronal survival, the impact of estradiol on Bcl-2 levels is ERK-independent. These findings support a model whereby estradiol acts via the classical estrogen receptors and IGF-I receptors, which converge on activation of ERK/MAPK signaling and CREB to promote neuronal survival in the face of global ischemia.

Gynecol Endocrinol. 2006 Oct;22(10):564-77

Hormone replacement therapy in menopausal women: Past problems and future possibilities.

Schmidt JW, Wollner D, Curcio J, Riedlinger J, Kim LS.

Southwest College Research Institute, Southwest College of Naturopathic Medicine, Tempe, Arizona, USA.

Oral administration of conjugated equine estrogens (CEE) with and without the synthetic progestin medroxyprogesterone acetate (MPA) in postmenopausal women is associated with side-effects that include increased risk of stroke and breast cancer. The current evidence that transdermal administration of estradiol may provide a safer alternative to orally administered CEE is reviewed. Transdermally administered estradiol has been shown to be an efficacious treatment for hot flushes possibly without the increase in blood clotting that is associated with administration of oral CEE. Further, natural progesterone may have a more beneficial spectrum of physiological effects than synthetic progestins. The substantial differences between CEE compared with estradiol and estriol, as well as the differences between synthetic MPA and natural progesterone, are detailed. Estriol is an increasingly popular alternative hormone therapy used for menopausal symptoms. There is evidence that estriol, by binding preferentially to estrogen receptor-beta, may inhibit some of the unwanted effects of estradiol. New clinical trials are needed to evaluate the safety and efficacy of topically or transdermally administered combinations of estradiol, estriol and progesterone. Future studies should focus on relatively young women who begin estrogen supplement use near the start of menopause.

Am J Epidemiol. 2006 Nov 28; [Epub ahead of print]

Zhang SM, Manson JE, Rexrode KM, Cook NR, Buring JE, Lee IM.

The authors conducted a prospective cohort analysis in the Women's Health Study (1992-2004), a completed randomized trial assessing aspirin and vitamin E in the primary prevention of cancer and cardiovascular disease, to evaluate use of oral conjugated estrogen alone (0.625 mg/day) and breast cancer risk in a time-varying fashion. Over an average of 10 years of follow-up, 305 incident cases of breast cancer (258 invasive and 47 in situ cancers) were documented among 12,718 women aged 45 years or more who were either consistent current users of oral conjugated estrogen alone (0.625 mg/day) or never users of any type of postmenopausal hormones at baseline and during follow-up. The multivariable hazard ratios comparing "consistent current users" with "never users" were 1.11 (95% confidence interval: 0.79, 1.56) for total breast cancer and 1.13 (95% confidence interval: 0.77, 1.64) for invasive cases. No significant associations were observed for use of less than 8 and 8 years or more. Restricting the analyses to women with prior hysterectomy somewhat strengthened the associations, albeit still not significantly. These data, like those from the Women's Health Initiative, show no significant increase in breast cancer risk with use of oral conjugated estrogen alone (0.625 mg/day), but a small increase or decrease in risk cannot be excluded.

Int J Cancer. 2006 Nov 27; [Epub ahead of print]

Different types of postmenopausal hormone therapy and mammographic density in Norwegian women.

Bremnes Y, Ursin G, Bjurstam N, Lund E, Gram IT.

Institute of Community Medicine, University of Tromso, Tromso, Norway.

Postmenopausal hormone therapy (HT) is associated with increased risk of breast cancer. The HTs used in Scandinavia is associated with higher risk estimates than those used in most other countries. Mammographic density is one of the strongest risk factors for breast cancer, and possibly an intermediate marker for breast cancer. We decided to examine the relationship between use of different types of HT and mammographic density in Norwegian women. Altogether, 1,007 postmenopausal participants in the governmental mammographic screening program were asked about current and previous HT use. Mammograms were classified according to percent and absolute mammographic density. Overall, current users of HT had on average 3.6% higher mean percent mammographic density when compared with never users (p < 0.001). After adjustment for age at screening, number of children and BMI in a multivariate model, women using the continuous estradiol (E(2)) plus norethisterone acetate (NETA) combination had a mean percent mammographic density significantly higher than never users (6.1% absolute difference). Those using the continuous E(2) plus NETA combination had an 4.8% (absolute difference) higher mean percent mammographic density after <5 years of use when compared with never users, while the corresponding number for >/=5 years of use was 7% (p-trend < 0.001). We found similar associations when absolute mammographic density was used as the outcome variable. In summary, our study shows a statistical significant positive dose-response association between current use of the continuous E(2) plus NETA combination and both measures of mammographic density.

Psychol Health Med. 2006 Nov;11(4):461-9

The effect of hormone replacement therapy on mood and everyday memory in younger mid-life women.

Stephens C, Pachana NA, Bristow V.

School of Psychology, Massey University, Palmerston North, New Zealand.

Research on the effect of hormone replacement therapy (HRT) on both mood and memory indicates that oestrogen may enhance verbal memory in younger mid-aged women. This study examined the effect of HRT on everyday memory, while accounting for mood changes, in women between ages 40 and 60. A within-subjects comparison of 17 women, showed that mood, everyday memory, working memory, and delayed verbal memory improved after 3 months of HRT use. The improvement in memory was not mediated by mood, but changes in mood were moderated by exercise habits. The results suggest that verbal memory in particular may be enhanced by HRT in this age group, and everyday memory is an important construct to consider in future research.

Semana del 22 al 28 de Noviembre de 2006

Dr. Juan Enrique Blümel

Osteoporos Int. 2006 Nov 21; [Epub ahead of print] 

The effect of treatment with a thiazide diuretic for 4 years on bone density in normal postmenopausal women.

Bolland MJ, Ames RW, Horne AM, Orr-Walker BJ, Gamble GD, Reid IR.

Department of Medicine, University of Auckland, Auckland, New Zealand, osteo@auckland.ac.nz.

We performed a 2-year extension of our previous 2-year randomized controlled trial of the effects of hydrochlorothiazide on bone mineral density. The improvements in bone density seen in the first 2 years were sustained throughout the extension study. Thiazides provide a further option in the prevention of postmenopausal bone loss. INTRODUCTION: Thiazide diuretics reduce urinary calcium excretion and therefore might prevent osteoporosis. Previously we reported a 2-year randomized controlled trial of hydrochlorothiazide treatment in 185 postmenopausal women that showed positive benefits of hydrochlorothiazide on bone density. Here, we report the results of a 2-year extension to that study. METHODS: Of 185 healthy postmenopausal women, 122 agreed to continue in a double-blinded 2-year extension taking 50 mg hydrochlorothiazide or placebo daily. Measurements of bone density occurred every 6 months and of calcium metabolism at 2 and 4 years. RESULTS: The improvements in bone density seen in the first 2 years of the trial were sustained throughout the extension. There were significant between-groups differences in the change in bone density over 4 years at the total body (0.9%, P < 0.001), legs (1.0%, P = 0.002), mid-forearm (1.1%, P = 0.03), and ultradistal forearm (1.4%, P = 0.04). At the lumbar spine (0.9%, P = 0.76) and femoral neck (0.4%, P = 0.53) the between-groups differences did not reach statistical significance. CONCLUSIONS: Hydrochlorothiazide produces small positive benefits on cortical bone density that are sustained for at least the first 4 years of treatment. They provide a further option in the prevention of postmenopausal bone loss, especially for women with hypertension or a history of kidney stones.

Eur J Epidemiol. 2006 Nov 22; [Epub ahead of print] 

Validation of the Cummings' risk score; how well does it identify women with high risk of hip fracture: The Tromso Study.

Ahmed LA, Schirmer H, Fonnebo V, Joakimsen RM, Berntsen GK.

Institute of Community Medicine, University of Tromso, 9037, Tromso, Norway, Luai.Awad@ism.uit.no.

OBJECTIVE: We examined a two-step case-finding strategy where the Cummings' risk score (NEJM 1995) was applied in a population-based setting together with bone mineral density (BMD) measurements in order to validate its ability to identify women with high risk of hip fracture. METHODS: All Tromso women aged between 65 and 74 were invited to the Tromso Osteoporosis Study (TROST) together with a 5% random sample of women aged 75-84 years (n = 1410). All had forearm BMD measurements in 1994/95 and were followed for 5 years with respect to first hip fracture. A risk score was constructed matching the Cummings score as closely as possible. RESULTS: In all 759, 578 and 73 women had 0-2, 3-4 and 5+ risk factors, respectively. Women with 5+ risk factors had a 5-year hip fracture risk of 11% (95% confidence interval (CI) 3.7-18.2%). BMD screening applied to these women identified 74% of them as osteoporotic and 19% as osteopenic with, respectively, 5-year hip fracture risk of 13% and 7.1%. CONCLUSION: In a population different from the one the score was generated in, this simple risk score identifies a group of women with high risk of hip fractures. With no additional BMD measurements, those high-risk women could benefit from early intervention measures.

Clin Rheumatol. 2006 Nov 21; [Epub ahead of print] 

Quantitative ultrasound is better correlated with bone mineral density and biochemical bone markers in elderly women.

Lappa V, Dontas IA, Trovas G, Constantelou E, Galanos A, Lyritis GP.

Laboratory for Research of the Musculoskeletal System, School of Medicine, University of Athens, 10 Athinas Street, Kifissia, 14561, Greece, idontas@med.uoa.gr.

The association between quantitative ultrasound (QUS) and bone turnover in postmenopausal women of different ages is an area of continuous investigation. The aim of this study was to investigate the relationship of ultrasound parameters [broadband ultrasound attenuation (BUA) and speed of sound (SOS)] to bone mineral density (BMD) and biochemical markers of bone turnover in three age groups of postmenopausal women. One hundred and twenty-three postmenopausal Caucasian women were divided into three groups according to their age: group A, range 44-54 years, mean age (+/-SD) 48.3 +/- 2.3; group B, range 55-65 years, mean age 59.4 +/- 2.1; and group C, range 66-77 years, mean age 68.2 +/- 3.1. Ultrasound parameters were measured by the DTU-one imaging ultrasonometer in the calcaneus. BMD was assessed by dual-energy X-ray absorptiometry (DEXA) at the lumbar spine, femoral neck, and trochanter. Bone turnover was assessed by serum bone-specific alkaline phosphatase (BAP), urinary excretion of free deoxypyridinoline, N-telopeptides (NTX), and C-telopeptide breakdown products of type I collagen (CTX). QUS and BMD were significantly correlated in all sites, except hip BMD in group A. The most significant correlation was observed between BUA and femoral neck BMD in group C (r = 0.626, p < 0.01). BUA correlated significantly with BAP, NTX, and CTX (r = -0.434, -0.511, -0.478, respectively; p < 0.01), and SOS with BAP and NTX (r = -0.351 and -0.356, respectively; p < 0.05) only in group C. In groups A and B, ultrasound parameters did not correlate significantly to biochemical markers. Ultrasound parameters were better correlated to hip BMD and to biochemical markers of bone turnover in elderly postmenopausal women. These ultrasound measurements could be used as a screening test for bone status, either in nonambulatory third aged women or in those living in rural areas where attending medical centers with DEXA equipment and biochemical laboratories is difficult.

Cancer Epidemiol Biomarkers Prev. 2006 Nov;15(11):2086-92. 

Body size, mammographic density, and breast cancer risk.

Boyd NF, Martin LJ, Sun L, Guo H, Chiarelli A, Hislop G, Yaffe M, Minkin S.

Ontario Cancer Institute, 610 University Avenue, Suite 10-415, Toronto, Ontario, Canada M5G 2K9. boyd@uhnres.utoronto.ca.

BACKGROUND: Greater weight and body mass index (BMI) are negatively correlated with mammographic density, a strong risk factor for breast cancer, and are associated with an increased risk of breast cancer in postmenopausal women, but with a reduced risk in premenopausal women. We have examined the associations of body size and mammographic density on breast cancer risk. METHOD: We examined the associations of body size and the percentage of mammographic density at baseline with subsequent risk of breast cancer among 1,114 matched case-control pairs identified from three screening programs. The effect of each factor on risk of breast cancer was examined before and after adjustment for the other, using logistic regression. RESULTS: In all subjects, before adjustment for mammographic density, breast cancer risk in the highest quintile of BMI, compared with the lowest, was 1.04 [95% confidence interval (CI), 0.8-1.4]. BMI was associated positively with breast cancer risk in postmenopausal women, and negatively in premenopausal women. After adjustment for density, the risk associated with BMI in all subjects increased to 1.60 (95% CI, 1.2-2.2), and was positive in both menopausal groups. Adjustment for BMI increased breast cancer risk in women with 75% or greater density, compared with 0%, increased from 4.25 (95% CI, 1.6-11.1) to 5.86 (95% CI, 2.2-15.6). CONCLUSION: BMI and mammographic density are independent risk factors for breast cancer, and likely to operate through different pathways. The strong negative correlated between them will lead to underestimation of the effects on risk of either pathway if confounding is not controlled.

Actas Esp Psiquiatr. 2006 Nov-Dec;34(6):408-15. 

Gender differences in cognitive functions and influence of sex hormones.

Torres A, Gomez-Gil E, Vidal A, Puig O, Boget T, Salamero M.

Institut Clinic de Neurociencias, Servicio de Psiquiatria y Psicologia Clinica, Hospital Clinic, Universitat de Barcelona, Barcelona.

Objective. To review scientific evidence on gender differences in cognitive functions and influence of sex hormones on cognitive performance.p> Method. Systematical search of related studies identified in Medline. Results. Women outperform men on verbal fluency, perceptual speed tasks, fine motor skills, verbal memory and verbal learning. Men outperform women on visuospatial ability, mathematical problem solving and visual memory. No gender differences on attention and working memory are found. Researchers distinguish four methods to investigate hormonal influence on cognitive performance: a) patient with hormonal disorders; b) neuroimaging in individuals during hormone administration; c) in women during different phases of menstrual cycle, and d) in patients receiving hormonal treatment (idiopathic hypogonadotropic hypogonadism, postmenopausal women and transsexuals). The findings mostly suggest an influence of sex hormones on some cognitive functions, but they are not conclusive because of limitations and scarcity of the studies. Conclusions. There are gender differences on cognitive functions. Sex hormones seem to influence cognitive performance.

FASEB J. 2006 Nov 20; [Epub ahead of print] 

Progestins overcome inhibition of platelet aggregation by endothelial cells by down-regulating endothelial NO synthase via glucocorticoid receptors.

Zerr-Fouineau M, Chataigneau M, Blot C, Schini-Kerth VB.

*Departement de Pharmacologie et Physico-Chimie, UMR 7175-LC1, Universite Louis Pasteur de Strasbourg, France; andTheramex, Monaco.

Hormone replacement therapy with estroprogestin preparations is associated with an increased risk of venous and arterial thromboembolic events in postmenopausal women. This study examined whether progestins affect the formation of NO in endothelial cells, and, if so, to determine the underlying mechanism. Experiments were performed with human umbilical vein endothelial cells. Endothelial nitric oxide synthase (eNOS) expression was assessed by real-time polymerase chain reaction (PCR) and Western blot analysis, NO formation by electron spin resonance spectroscopy, nuclear translocation of the glucocorticoid receptor by immunofluorescence microscopy, and platelet aggregation by an aggregometer. Medroxyprogesterone acetate (MPA) and progesterone markedly decreased the eNOS mRNA and protein levels, whereas levonorgestrel and nomegestrol acetate had only small effects. This effect was associated with a decreased NO formation leading to a reduced ability of endothelial cells to prevent platelet aggregation and was prevented by knockdown of the glucocorticoid receptor using siRNA. MPA and progesterone, but not levonorgestrel and nomegestrol acetate, caused nuclear translocation of the glucocorticoid receptor. The present findings indicate that certain progestins, including MPA, reduce the antiaggregatory effect of endothelial cells by decreasing the expression of eNOS and the formation of NO in endothelial cells, an effect that is mediated via activation of glucocorticoid receptors.

Breast Cancer Res Treat. 2006 Nov 18; [Epub ahead of print] 

Parental age at delivery and incidence of breast cancer: a prospective cohort study.

Xue F, Colditz GA, Willett WC, Rosner BA, Michels KB.

Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA.

BACKGROUND: Studies on parental age at delivery in relation to breast cancer risk have had mixed results, but prospective data are limited. No study has explored the associations with subtypes of breast cancer defined by hormonal receptor status. METHODS: 109,773 women in the Nurses' Health Study were followed from 1976 to 2002. We used Cox proportional hazards model to examine the association between parental age at delivery and daughters' risk of breast cancer. RESULTS: 6,827 incident cases of invasive breast cancer occurred in this cohort during 2,581,098 person-years. Adjusting for other early life exposures and family history of breast cancer, the hazard ratio for breast cancer in women born to mothers aged 21-25, 26-30, 31-35, and >/=36 years was, respectively, 1.08 (95% CI: 0.99-1.18), 1.12 (95% CI: 1.03-1.23), 1.17 (95% CI: 1.06-1.29), and 1.12 (95% CI: 1.01-1.25), compared to women born to mothers aged </=20 years (P for trend = 0.008). Similarly, advanced paternal age was associated with increased incidence of breast cancer (P for trend = 0.03), but the association disappeared when conditioning on maternal age. The positive association between maternal age and incidence of breast cancer was stronger for estrogen receptor-positive and progesterone receptor-positive tumors (P for trend = 0.003) than for tumors with both receptors negative (P for trend = 0.78), and was more consistent among postmenopausal women, women without a family history and women who were first born. CONCLUSION: Our findings support a modest positive association between maternal age and daughter's risk of breast cancer, possibly mediated by hormonal factors.

Med Hypotheses. 2006 Nov 17; [Epub ahead of print]

Lipid peroxidation and the protective effect of physical exercise on breast cancer.

Gago-Dominguez M, Jiang X, Esteban Castelao J.

USC/Norris Comprehensive Cancer Center, Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033-0800, United States.

Physical exercise has been found to decrease the risk of breast cancer by undefined means. In our prior communication, we proposed lipid peroxidation to be a relevant mechanism for breast cancer protection associated with many established protective factors such as parity, oophorectomy, menopause, physical exercise, etc. [Gago-Dominguez M, Castelao J, Pike MC, Sevanian A, Haile RW. Role of lipid peroxidation in the epidemiology and prevention of breast cancer. Cancer Epidemiol Biomark Prevent 2005;14:2829-39]. In the present communication, we examine in detail the physical exercise-breast cancer relationship in light of the lipid peroxidation mechanism. We provide additional supporting evidence for the hypothesis that oxidative stress-induced apoptosis may be a mechanism responsible, at least in part, for the protective effect of exercise in breast cancer. Specifically, we describe (1) the sources of free radicals occurring during exercise, (2) existing experimental data on physical exercise, lipid peroxidation and cancer, (3) existing supporting data implicating exercise-induced reactive oxygen species (ROS) as the mechanism responsible for increased apoptosis in different cell systems, and (4) changes in the antioxidant enzymes glutathione S transferases (GSTs), superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) that occur after physical exercise, which are believed to be a physiologic response to oxidative stress induced by physical exercise.

Bone. 2006 Nov 15; [Epub ahead of print] 

Associations of vitamin D status with bone mineral density, bone turnover, bone loss and fracture risk in healthy postmenopausal women. The OFELY study.

Garnero P, Munoz F, Sornay-Rendu E, Delmas PD.

Synarc 16 rue Montbrillant 69003, Lyon France.

INTRODUCTION: Vitamin D status is considered as an important determinant of bone health but supplementation trials with vitamin D(3) have yielded conflicting results. The aim of this study was to investigate the associations between serum 25-hydroxyvitamin D (25-OH D), bone turnover markers, bone mineral density (BMD), radius bone loss and incidence of fracture in postmenopausal women. METHODS: 669 postmenopausal women (mean age: 62.2 years) belonging to a population-based cohort were followed prospectively for a median of 11.2 years. At baseline, 25-OH D levels, BMD, bone turnover markers and clinical risk factors of osteoporosis were assessed. BMD loss at the radius was estimated by annual measurements of BMD and all incident fractures which occurred in 134 women were confirmed by radiographs. RESULTS: 73% and 35% of women had serum 25-OH D levels below 75 and 50 nmol/l which correspond respectively to the median and lowest optimal values recently proposed for fracture prevention. 11% of women had levels below 30 nmol/l. Serum 25-OH D correlated modestly with intact PTH (r(2)=0.023, p<0.0001), but not with bone turnover markers or BMD at the hip and radius after adjustment for age. When levels of 25-OH D were considered as a continuous variable, there was no significant association between 25-OH D levels and radius BMD loss or fracture risk. After adjustment for age, there was no significant difference in incidence of fracture, BMD, radius BMD loss, bone turnover markers, grip strength and the percentage of fallers in the previous year between women with 25-OH D levels below or above 75, 50 or 30 nmol/l. CONCLUSIONS: In a population of home-dwelling healthy postmenopausal women with few of them with severe vitamin D deficiency, vitamin D status may not be an important determinant of bone health.

Curr Osteoporos Rep. 2006 Dec;4(4):134-9.

Osteoporosis and depression: a historical perspective.

Gold DT, Solimeo S.

Departments of Psychiatry and Behavioral Sciences, Sociology, and Psychology; Center for the Study of Aging and Human Development, Box 3003, Duke University Medical Center, Durham, NC 27710, USA. dtg@geri.duke.edu.

In the early 1980s, researchers studying osteoporosis noted that depression was one of the major negative consequences of bone loss and fractures. These researchers believed that osteoporosis and fractures occurred first, causing a reactive depression. Meanwhile, a similar but distinct psychiatry literature noted that osteoporosis or bone loss appeared to be an undesirable consequence of major depression. Here, depression was seen as the causal factor, and osteoporosis was the outcome. The psychiatric perspective is more biological, based on the presence of hypercorticoidism in depressed individuals. Those who believe that osteoporosis leads to depression point out that depression is a consequence of many chronic illnesses. Regardless of the correct causal order, the strong positive relationship between osteoporosis and depression merits further clinical and research attention in the future.

Cancer Causes Control. 2006 Dec;17(10):1281-90.

Breast cancer risk factors in relation to breast density (United States).

Titus-Ernstoff L, Tosteson AN, Kasales C, Weiss J, Goodrich M, Hatch EE, Carney PA.

Dartmouth-Hitchcock Medical Center, One Medical Center, Dr. HB 7926 , Lebanon, NH, 03756, USA.

OBJECTIVES: Evaluate known breast cancer risk factors in relation to breast density. METHODS: We examined factors in relation to breast density in 144,018 New Hampshire (NH) women with at least one mammogram recorded in a statewide mammography registry. Mammographic breast density was measured by radiologists using the BI-RADS classification; risk factors of interest were obtained from patient intake forms and questionnaires. RESULTS: Initial analyses showed a strong inverse influence of age and body mass index (BMI) on breast density. In addition, women with late age at menarche, late age at first birth, premenopausal women, and those currently using hormone therapy (HT) tended to have higher breast density, while those with greater parity tended to have less dense breasts. Analyses stratified on age and BMI suggested interactions, which were formally assessed in a multivariable model. The impact of current HT use, relative to nonuse, differed across age groups, with an inverse association in younger women, and a positive association in older women (p < 0.0001 for the interaction). The positive effects of age at menarche and age at first birth, and the inverse influence of parity were less apparent in women with low BMI than in those with high BMI (p = 0.04, p < 0.0001 and p = 0.01, respectively, for the interactions). We also noted stronger positive effects for age at first birth in postmenopausal women (p = 0.004 for the interaction). The multivariable model indicated a slight positive influence of family history of breast cancer. CONCLUSIONS: The influence of age at menarche and reproductive factors on breast density is less evident in women with high BMI. Density is reduced in young women using HT, but increased in HT users of age 50 or more.

Cancer Causes Control. 2006 Dec;17(10):1227-35.

Do breast cancer risk factors modify the association between hormone therapy and mammographic breast density? (United States).

Aiello EJ, Buist DS, White E.

Group Health Center for Health Studies, 1730 Minor Ave, Suite 1600, Seattle, WA, 98101, USA, aiello.e@ghc.org.

OBJECTIVE: To evaluate whether the association between hormone therapy (HT) and breast density differs by levels of breast cancer risk factors. METHODS: We evaluated 80,867 screening mammograms from 39,296 postmenopausal women from Washington State. We estimated odds ratios and 95% confidence intervals for dense breasts (Breast Imaging Reporting and Data System categories 3 "heterogeneously dense" and 4 "extremely dense") compared to fatty breasts (categories 1 "almost entirely fat" and 2 "scattered fibroglandular") among HT users compared to never users. We separately examined former HT use and current HT use by type (estrogen plus progestin therapy (EPT) and estrogen-only therapy (ET)). We stratified the associations by age, BMI, race, family history, and reproductive and menopausal factors. RESULTS: Current EPT users had a 98% (1.87-2.09) greater odds of having dense breasts and current ET users had a 71% (1.56-1.87) greater odds compared to never users. Current HT users were more likely to have dense breasts if they were older, had more children, or younger at first birth compared to never users; these associations were stronger among EPT users than ET users. CONCLUSIONS: HT, particularly EPT, may reduce protective effects of older age, parity, and younger age at first birth on mammographic density.

Exp Gerontol. 2006 Nov 14; [Epub ahead of print]

Advances in endocrinology of aging research, 2005-2006.

Bellino FL.

Biology of Aging Program, National Institute on Aging Bethesda, MD 20891, USA.

The purpose of this brief review is to highlight some of the more important advances in endocrinology of aging research over the past year. Four advances were chosen and briefly described. First, exploration of the early steps in the generation of the internal steroidal hormonal signal involved in lifespan extension via the insulin/IGF-like signaling pathway in the nematode by two research groups revealed that the product of cholestanoic acid derivatives metabolized by a cytochrome P-450-like protein activates a protein with homology to the mammalian nuclear receptor superfamily, a process strikingly similar to the steroid hormone signaling pathway documented in mammalian systems. Second is the discovery that sirtuins, proteins that regulate lifespan in model organisms, enhance pancreatic insulin secretion in mice following a glucose challenge, suggesting the potential to regulate mammalian lifespan through regulation of the insulin signaling pathway. Third, the newly discovered hormone klotho, which also plays a role in regulating lifespan, in this case in mice, is reported to not only negatively affect insulin sensitivity but, perhaps more importantly, significantly affects calcium and phosphate metabolism as a required cofactor of Fgf-23 signaling. Finally the gonadotropin FSH is shown to directly affect bone density in mice separate from any direct effect of estrogen, suggesting that reproductive hormones other than estrogen can directly impact menopause-associated pathophysiology in non-reproductive tissues.

Fundam Clin Pharmacol. 2006 Dec;20(6):539-48

Understanding the oestrogen action in experimental and clinical atherosclerosis.

Arnal JF, Douin-Echinard V, Brouchet L, Tremollieres F, Laurell H, Lenfant F, Gadeau AP, Guery JC, Gourdy P.

INSERM U589, IFR 31, CHU Toulouse-Rangueil, BP 84225, 31432 Toulouse Cedex 4, France.

Whereas hormone replacement/menopause therapy (HRT) in postmenopausal women increases the coronary artery risk, epidemiological studies (protection in premenopaused women) suggest and experimental studies (prevention of the development of fatty streaks in animals) demonstrate a major atheroprotective action of oestradiol (E2). The understanding of the deleterious and beneficial effects of oestrogens is thus required. The immuno-inflammatory system plays a key role in the development of fatty streak deposit as well as in the rupture of the atherosclerotic plaque. Whereas E2 favours an anti-inflammatory effect in vitro (cultured cells), it rather elicits in vivo a proinflammation at the level of several subpopulations of the immuno-inflammatory system, which could contribute to plaque destabilization. Endothelium is another important target for E2, as it potentiates endothelial NO and prostacyclin production, thus promoting the beneficial effects as vasorelaxation and inhibition of platelet aggregation. Prostacyclin, but not NO, appears to be involved in the atheroprotective effect of E2. E2 also accelerates endothelial regrowth, thus favouring vascular healing. Finally, most of these effects of E2 are mediated by oestrogen receptor alpha, and are independent of oestrogen receptor beta. In summary, a better understanding of the mechanisms of oestrogen action not only on the normal and atheromatous arteries, but also on innate and adaptive immune responses is required and should help to optimize the prevention of cardiovascular disease after menopause. These mouse models should help to screen existing and future selective oestrogen receptor modulators.

Semana del 8 al 21 de Noviembre de 2006

Dr. Juan Enrique Blümel

Osteoporos Int. 2006 Nov 16; [Epub ahead of print]

Links between cardiovascular disease and osteoporosis in postmenopausal women: serum lipids or atherosclerosis per se?

Bagger YZ, Rasmussen HB, Alexandersen P, Werge T, Christiansen C, Tanko LB; PERF study group.

Center for Clinical and Basic Research A/S, Ballerup Byvej 222, DK-2750, Ballerup, Denmark.

INTRODUCTION AND HYPOTHESIS: Epidemiological observations suggest links between osteoporosis and risk of acute cardiovascular events and vice versa. Whether the two clinical conditions are linked by common pathogenic factors or atherosclerosis per se remains incompletely understood. We investigated whether serum lipids and polymorphism in the ApoE gene modifying serum lipids could be a biological linkage. METHODS: This was an observational study including 1176 elderly women 60-85 years old. Women were genotyped for epsilon (varepsilon) allelic variants of the ApoE gene, and data concerning serum lipids (total cholesterol, triglycerides, HDL-C, LDL-C, apoA1, ApoB, Lp(a)), hip and spine BMD, aorta calcification (AC), radiographic vertebral fracture and self-reported wrist and hip fractures, cardiovascular events together with a wide array of demographic and lifestyle characteristics were collected. RESULTS: Presence of the ApoE varepsilon4 allele had a significant impact on serum lipid profile, yet no association with spine/hip BMD or AC could be established. In multiple regression models, apoA1 was a significant independent contributor to the variation in AC. However, none of the lipid components were independent contributors to the variation in spine or hip BMD. When comparing the women with or without vertebral fractures, serum triglycerides showed significant differences. This finding was however not applicable to hip or wrist fractures. After adjustment for age, severe AC score (>/=6) and/or manifest cardiovascular disease increased the risk of hip but not vertebral or wrist fractures. CONCLUSION: The contribution of serum lipids to the modulators of BMD does not seem to be direct but rather indirect via promotion of atherosclerosis, which in turn can affect bone metabolism locally, especially when skeletal sites supplied by end-arteries are concerned. Further studies are needed to explore the genetic or environmental risk factors underlying the association of low triglyceride levels to vertebral fractures.

Menopause. 2006 Nov 13; [Epub ahead of print]

Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in postmenopausal women.

Hofling M, Hirschberg AL, Skoog L, Tani E, Hagerstrom T, von Schoultz B.

From the Departments of 1Obstetrics and Gynecology and 2Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden, Stockholm, Sweden.

OBJECTIVE:: During the past few years serious concern has been raised about the safety of combined estrogen/progestogen hormone therapy, in particular about its effects on the breast. Several observations suggest that androgens may counteract the proliferative effects of estrogen and progestogen in the mammary gland. Thus, we aimed to study the effects of testosterone addition on breast cell proliferation during postmenopausal estrogen/progestogen therapy. DESIGN:: We conducted a 6-month prospective, randomized, double-blind, placebo-controlled study. A total of 99 postmenopausal women were given continuous combined estradiol 2 mg/norethisterone acetate 1 mg and were equally randomly assigned to receive additional treatment with either a testosterone patch releasing 300 mug/24 hours or a placebo patch. Breast cells were collected by fine needle aspiration biopsy at baseline and after 6 months, and the main outcome measure was the percentage of proliferating breast cells positively stained by the Ki-67/MIB-1 antibody. RESULTS:: A total of 88 women, 47 receiving active treatment and 41 in the placebo group, completed the study. In the placebo group there was a more than fivefold increase (P < 0.001) in total breast cell proliferation from baseline (median 1.1%) to 6 months (median 6.2%). During testosterone addition, no significant increase was recorded (1.6% vs 2.0%). The different effects of the two treatments were apparent in both epithelial and stromal cells. CONCLUSIONS:: Addition of testosterone may counteract breast cell proliferation as induced by estrogen/progestogen therapy in postmenopausal women.

Menopause. 2006 Nov 13; [Epub ahead of print]

Sex hormone ratio changes in men and postmenopausal women with coronary artery disease.

He H, Yang F, Liu X, Zeng X, Hu Q, Zhu Q, Tu B.

From the 1Department of Cardiology, Qilu Hospital, University of Shandong, Jinan, China; 2Institute of Clinical Molecular Biology, University of Shandong, Jinan, China; and 3Institute of Neurology, Ruijin Hospital (affiliated with Shanghai Jiao Tong University), Shanghai, China.

OBJECTIVE:: The goal of this study was to investigate the potential role of sex hormones in coronary atherosclerosis in both men and postmenopausal women. DESIGN:: A total of 258 male and 236 female postmenopausal participants with angiographically defined stable coronary artery disease (CAD) were enrolled. We measured the levels of estradiol (E2), progesterone (P), testosterone (T), follicle-stimulating hormone, and luteinizing hormone in the participants and in 156 male and 132 female disease-free and age-matched controls using commercially available radioimmunoassay kits. RESULTS:: In the male study participants and control subjects, the levels of E2 and P differed slightly in opposing directions; however, these differences were not significantly different, nor were there significant differences in T. However, the ratio of E2 to P in participants was significantly (P < 0.01) lower (even after adjustments for age and body mass index) than in the control subjects (mean +/- SEM: 70.2 +/- 56.4 vs 90.7 +/- 59.5, respectively). In the postmenopausal women, a slight decrease in E2 and increases in P and T in participants were not significantly different from levels in the control group. However, the E2 to P and E2 to T ratios were significantly (P < 0.01) lower (before and after adjustments for age and body mass index adjustments) in the participants relative to the control subjects (38.7 +/- 28.4 vs 49.6 +/- 36.3 and 46.5 +/- 37.6 vs 60.6 +/- 40.8, respectively). Correlation analyses demonstrated that the sex hormone ratio changes in both men and postmenopausal women were related with atherogenic blood lipoprotein changes. In both the male and female groups, levels of follicle-stimulating hormone and luteinizing hormone did not differ significantly between the participants and controls, and correlation analyses revealed no association between these hormones and the ratio of E2 to P in males and the ratios of E2 to P and E2 to T in females (r < 0.2, P > 0.05). Multiple regression analyses demonstrated that age and the presence of CAD were significantly and independently associated with the E2-to-P ratio in men and the E2-to-P and E2-to-T ratios in women and that E2-to-P ratio and low-density lipoprotein cholesterol level were significant independent predictors of CAD in males; E2-to-P and E2-to-T ratios and low-density lipoprotein cholesterol level were significant predictors of CAD in women. CONCLUSIONS:: In both men and postmenopausal women with angiographic CAD, there were significant differences (relative to age-matched control subjects) in sex hormone ratios, suggesting an abnormality that could influence coronary health. A lower E2-to-P ratio may be associated with the male disposition to coronary atherosclerosis, whereas lower E2-to-P and E2-to-T ratios may be associated with the same condition in females.

Treat Endocrinol. 2006;5(6):375-383

Optimizing the Benefits of Bisphosphonates in Osteoporosis : The Importance of Appropriate Calcium Intake.

Boonen S, Bouillon R, Haentjens P, Vanderschueren D.

Leuven University Center for Metabolic Bone Diseases, Katholieke Universiteit Leuven, Leuven, BelgiumDivision of Geriatric Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.

Osteoporosis is a major cause of morbidity, mortality, and healthcare costs. The socioeconomic burden of osteoporosis is likely to increase dramatically if improvements in prevention are not made. Calcium supplementation effectively reduces the rate of bone loss in postmenopausal women, yet most women do not achieve an adequate calcium intake. In fact, use of calcium supplementation appears to have declined as the more effective antiresorptive therapies, such as bisphosphonates, have become available. Among patients prescribed bisphosphonates, calcium intake is often insufficient, despite the fact that adequate calcium intake may be necessary to gain the maximum benefits from antiresorptive therapy. In addition, because calcium interferes with bisphosphonate absorption, incorrect use of calcium may limit the efficacy of bisphosphonate therapy. This underscores the need for new initiatives to reduce the confusion surrounding appropriate calcium use during antiresorptive therapy. Co-packaging of bisphosphonates with calcium supplements is one strategy to help ensure that patients taking bisphosphonates not only achieve adequate calcium intake but also gain the maximum benefit from bisphosphonate therapy.

Eur J Cancer Prev. 2006 Dec;15(6):490-492

Estrogen-progestogen replacement therapy and ovarian cancer: an update.

Vecchia CL.

aIstituto di Ricerche Farmacologiche 'Mario Negri' bIstituto di Statistica Medica e Biometria, Universita degli Studi di Milano, Milan, Italy.

Hormone replacement therapy in menopause has been associated with a moderate increase in ovarian cancer risk. Data on combined estrogen-progestin therapy, based on one randomized trial, two cohort and four case-control studies, do not provide definite evidence of an association between combined hormone replacement therapy and ovarian cancer. These data do not suggest, however, substantial differences between the effect of estrogen only or unspecified hormone replacement therapy and combined hormone replacement therapy on ovarian cancer risk.

Menopause. 2006 November/December;13(6):862-877

The role of calcium in peri- and postmenopausal women: 2006 position statement of The North American Menopause Society.

[No authors listed]

OBJECTIVE:: To update the evidence-based consensus opinion published by The North American Menopause Society (NAMS) in 2001 on the role of calcium in peri- and postmenopausal women. DESIGN:: NAMS followed the general principles established for evidence-based guidelines to create this document. A panel of clinicians and researchers acknowledged to be experts in the field of calcium and women's health was enlisted to review the previous position statement and data published since then, compile supporting statements, and make recommendations. Their advice was used to assist the NAMS Board of Trustees in publishing this position statement. RESULTS:: Adequate calcium intake (in the presence of adequate vitamin D status) has been shown to reduce bone loss in peri- and postmenopausal women and reduce fractures in postmenopausal women older than age 60 with low calcium intakes. Adequate calcium is considered a key component of any bone-protective therapeutic regimen. Calcium has also been associated with beneficial effects in several nonskeletal disorders, primarily hypertension, colorectal cancer, obesity, and nephrolithiasis, although the extent of those effects has not been fully elucidated. The calcium requirement rises at menopause. The target calcium intake for most postmenopausal women is 1,200 mg/day. Adequate vitamin D status, defined as 30 ng/mL or more of serum 25-hydroxyvitamin D (usually achieved with a daily oral intake of at least 400 to 600 IU), is required to achieve the nutritional benefits of calcium. The best source of calcium is food, and the best food source is dairy products. High-quality calcium supplements (taken in divided doses) are alternative sources for women unable to consume enough dietary calcium. There are no reported cases of calcium intoxication from food sources, and cases associated with supplements are rare (high intake levels of 2,150 mg/day have resulted in a 17% increase in renal calculi in one recent study, but not others). Because no accurate test to determine calcium deficiency exists, clinicians should focus instead on encouraging women to consume enough calcium to meet the recommended levels. CONCLUSIONS:: The most definitive role for calcium in peri- and postmenopausal women is in bone health, but, like most nutrients, calcium has beneficial effects in many body systems. Based on the available evidence, there is strong support for the importance of ensuring adequate calcium intake in all women, particularly those in peri- or postmenopause.

              

J Med Assoc Thai. 2006 Sep;89(9):1362-7.

Randomized comparison of lower and standard dosages of transdermal estradiol on serum estradiol levels and vaginal maturation index.

Rungruxsirivorn T, Panyakamlerd K, Trerattanachart S, Taechakraichana N.

Department of Obstetrics and Gynecology, Chulalongkorn University, Bangkok 10330, Thailand.

OBJECTIVE: To evaluate serum estradiol (E2) in postmenopausal women who received 0.025 mg/d or 0.05 mg/d transdermal estradiol, in an equivalent trial. MATERIAL AND METHOD: One hundred and eight postmenopausal women were randomized into 0.025 mg/d and 0.05 mg/d of transdermal E2 matrix patch. After 12 weeks, serum E2 and vaginal maturation index (VMI) were checked in both groups. Adverse effects, such as breast tenderness, application site reaction, weight gain, and headache, were also assessed. RESULTS: Serum E2 in 0.025 mg/d and 0.05 mg/d groups were 42.43 +/- 35.11 and 48.41 +/- 22.36 pg/mL, respectively. There was no statistically significant difference between the groups. Equivalence was found under CI of +/- 14 pg/mL. Mean value of superficial cells and vaginal maturation index (VMI) were comparable between both groups. Adverse effects seem to be less in the lower dosage group compared to the standard dosage group. CONCLUSION: The lower dosage (0.025 mg/d) of the transdermal E2 matrix system is probably an appropriate treatment option for postmenopausal women who need minimal effective and minimal adverse effects.

J Clin Densitom. 2006 Oct-Dec;9(4):413-8. Epub 2006 Sep 1

What is the Number of Older Canadians Needed to Screen by Measurement of Bone Density to Detect an Undiagnosed Case of Osteoporosis? A Population-Based Study From CaMos.

Sawka AM, Papaioannou A, Josse RG, Murray TM, Ioannidis G, Hanley DA, Prior JC, Thabane L, Papadimitropoulos EA, Gafni A, Pickard L, Anastassiades T, Kirkland S, Adachi JD, The Camos Research Group.

Department of Medicine, Division of Endocrinology, University of Toronto, Toronto, Ontario; Department of Medicine, Division of Endocrinology, University Health Network, Toronto, Ontario.

Routine bone mineral densitometry (BMD) screening has been recommended for women aged >/=65 yr (Osteoporosis Canada [OC], International Society for Clinical Densitometry [ISCD], Canadian and United States Task Forces on Preventative Healthcare, and National Osteoporosis Foundation) and for men >/=65 yr (OC) or >/=70 yr (ISCD). We estimated the number of older Canadians needed to screen (NNS) by BMD to detect an undiagnosed case of osteoporosis, using prospective, multicenter, population-based data from the Canadian Multicentre Osteoporosis Study (CaMos). We included participants aged >/=65 yr with baseline dual-energy X-ray absorptiometry (DXA) BMDs at the femoral neck and lumbar spine (L1-L4). Osteoporosis was defined by a T-score </=2.5 at either site. Patients were questioned about a prior diagnosis of osteoporosis. We studied 2699 women and 1032 men aged >/=65 yr. The percentage prevalence and 95% confidence intervals were determined. In individuals aged >/=65 yr, the prevalence of osteoporosis was 25.6% in women (95% confidence interval, 24.0%, 27.3%) and 8.9% in men (7.3%, 10.8%). In 652 men aged >/=70 yr, the prevalence of osteoporosis was 11.3% (9.1%, 14.0%). Of the participants with BMD-defined osteoporosis, 76.6% of woman aged >/=65 yr (73.2%, 79.6%; 516 of 674 women), 93.4% of men aged >/=65 yr (86.4%, 96.9%; 85 of 91), and 93.2% of men >/=70 yr (84.9%, 97.0%; 68 of 73) were not aware of it. Thus, the minimum NNS by BMD testing to detect one previously undiagnosed case of osteoporosis in Canada is: 6 women aged >/=65 yr, 13 men aged >/=65 yr, and 10 men aged >/=70 yr.

Maturitas. 2006 Nov 6; [Epub ahead of print]

Hormonal influence on periurethral vessels in postmenopausal incontinent women using Doppler velocimetry analysis.

Jarmy-Di Bella ZI, Girao MJ, Di Bella V, Sartori MG, Szejnfeld J, Baracat EC, Lima GR.

Department of Gynecology at Escola Paulista de Medicina, Federal University of Sao Paulo, Brazil.

The lack of estrogen affects the urinary tract mainly by diminishing vascular, muscular and epithelial trophism, resulting in negative effects on continence in postmenopausal women. OBJECTIVE: Study the effect of hormone therapy (estrogen and progesterone) in periurethral vessels detected by Doppler velocimetric analysis using, as parameters, the number of vessels, resistance and pulsatility indexes, as well as the minimum diastolic value. METHODS: Thirty-eight postmenopausal women with stress urinary incontinence were randomized into two groups. The first consisted of women receiving 3 months of estrogen therapy previous to 3 months of continuous estrogen and progesterone combined therapy. The second comprised of women receiving 3 months of continuous estrogen and progesterone therapy. Periurethral Doppler velocimetric analysis was done before hormone administration and during treatment in both groups. RESULTS: We observed a statistically significant increased number of periurethral vessels during treatment in both groups. There was an increase in value of the mean minimum diastolic value during estrogen and progesterone therapy in Group 2. The resistance indexes diminished in both groups. However, they were not statistically significant. CONCLUSION: Hormonal therapy of short duration (3-6 months) had a positive effect on the urethral continence mechanism increasing the number of periurethral vessels either with estrogen alone or combined therapy (estrogen and progesterone).

Dan Med Bull. 2006 Aug;53(3):349-53

Sexual dysfunction in the peri- and postmenopause. Status of incidence, pharmacological treatment and possible risks. A secondary publication.

Gregersen N, Jensen PT, Giraldi AE.

Department of Urology, Aalborg Hospital, Aarhus University Hospital, Denmark.

The frequency of female sexual dysfunction increases with age, and the menopausal transition has a negative effect on the sexuality. Pharmacological treatment options for female sexual dysfunction during the peri- and post-menopause include hormone therapy or sildenafil. A limited number of randomized, controlled trials have been conducted and evidence suggests that systemic hormone therapy with estrogen, estrogen/progesterone, estrogen/testosterone and tibolone have a positive impact on sexual dysfunction during the peri- and postmenopause. Further, there is evidence that treatment with local estrogen relieves vaginal dryness and dyspareunia. Recent knowledge on side effects related to hormone therapy necessitates careful evaluation of the indication for hormone therapy and the duration of postmenopausal hormone therapy should be as short as possible. Long-term side effects of testosterone have not yet been fully investigated. A positive effect of sildenafil has been observed in a limited group of women; those with arousal problems but with no desire problems. The results suggest an intensified focus on new pharmaceutical products for the treatment of female sexual dysfunction in the postmenopause. For the time being the effect of testosterone therapy and tibolone on female sexual dysfunction is being investigated. Sexual dysfunction in women (Female Sexual Dysfunction, FSD) is multi-factorial and influenced by physiological, psychological, social and emotional factors. FSD is defined in four diagnostic groups: desire-, arousal-, orgasm- and pain problems. Recently, it has been suggested that the woman herself should assess the dysfunction as distressful to be diagnosed as having a sexual dysfunction [1]. There are only a limited number of well-conducted population surveys on the prevalence of FSD. Further, relatively few randomized, controlled trials of pharmacological treatment of FSD have been carried out.

Osteoporos Int. 2006 Nov 8; [Epub ahead of print]

Bone density in relation to alcohol intake among men and women in the United States.

Wosje KS, Kalkwarf HJ.

Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7035, Cincinnati, OH, 45229, USA.

Studies of postmenopausal women have shown a positive association between BMD and alcohol intake. We found that BMD was higher in men, and possibly postmenopausal women, who drank alcohol compared with those who abstained. Drinking alcohol, but not binge drinking, may benefit bone health of men and postmenopausal women. INTRODUCTION: Osteoporotic fractures account for over 2.5 million physician visits annually for persons ages >/=45 years in the United States. Studies of postmenopausal women show a positive association between bone mineral density (BMD) and alcohol intake, but for men and premenopausal women, the bone-alcohol relationship remains unclear. We examined the association between total hip (TH) and femoral neck (FN) BMD and alcohol intake of men and pre- and postmenopausal women. METHODS: We conducted multiple regression analyses using data from 13,512 persons ages >/=20 years from the Third National Health and Nutrition Examination Survey, 1988-1994. Alcohol intake and binge drinking were measured by questionnaire and hip BMD by dual energy X-ray absorptiometry (DXA). RESULTS: Accounting for covariates, TH BMD was higher in men (n = 6,868) who had 5-29 (+2.1%, p < 0.01) and >29 drinking occasions/month (+1.7%, p < 0.05) than men who abstained. BMD of premenopausal women (n = 4,136) who drank alcohol did not differ from those who abstained. FN BMD was 3.8% higher in postmenopausal women (n = 2,043) who had >29 drinking occasions/month than those who abstained (p = 0.06). Binge drinking was not associated with BMD of men or women. CONCLUSIONS: Drinking alcohol, but not binge drinking, appears to be beneficial to bone health of men and possibly postmenopausal women.

Menopause. 2006 Nov 3; [Epub ahead of print]

Early postmenopausal hormone therapy improves postural balance.

Naessen T, Lindmark B, Lagerstrom C, Larsen HC, Persson I.

Departments of Women's and Children's Health, Section for Obstetrics and Gynecology, 2Neuroscience, Section of Physiotherapy, and 3Otorhinolaryngology-Audiology, University Hospital, Uppsala, Sweden.

OBJECTIVE:: Postmenopausal hormone therapy (HT) results in more substantial reductions in the risk of hip fracture when initiated sooner rather than later after menopause. We studied the effects of postmenopausal HT on the postural balance of postmenopausal women, with further assessment according to the time since they achieved menopause. DESIGN:: One hundred women with a mean age of 52.5 years (91 evaluable) were randomly and blindly assigned to either a sequential estradiol-norethisterone acetate regimen or placebo for 3 months, after which all participants received open HT for a further 3 months. Postural balance was assessed as sway velocity using a force platform. RESULTS:: After 3 months of HT, sway velocity had improved (decreased) from baseline by 7.0% (P = 0.007 vs baseline and P = 0.038 vs placebo). Continued HT for 6 months further improved sway velocity by 12% from baseline (P < 0.0001) to reach values similar to those historically found in younger women or in postmenopausal women after long-term HT. Closer proximity to menopause and more pronounced increases in serum estradiol values were associated with stronger improvements in sway velocity (P = 0.018 for interaction). HT also improved dizziness (P = 0.016 vs baseline and 0.022 vs placebo). (Nonparametric statistics are used throughout, except for analyses of interaction and dizziness.) CONCLUSIONS:: Initiation of HT soon after menopause rapidly improved postural balance to levels normally seen in young women. We suggest that improved postural balance can contribute to the protection against fractures associated with HT and explain the more substantial reduction in hip fracture risk after HT initiated sooner, compared with later, after menopause. Further study is required to confirm these results.

J Womens Health (Larchmt). 2006 Oct;15(8):962-74

Lifestyle intervention and coronary heart disease risk factor changes over 18 months in postmenopausal women: the Women On the Move through Activity and Nutrition (WOMAN study) clinical trial.

Kuller LH, Kinzel LS, Pettee KK, Kriska AM, Simkin-Silverman LR, Conroy MB, Averbach F, Pappert WS, Johnson BD.

Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.

OBJECTIVES: In this paper, we present the results of changes in risk factors by use of hormone therapy (HT) at 18 months in the Women On the Move through Activity and Nutrition (WOMAN) randomized trial. METHODS: The trial was designed to test the hypothesis that aggressive dietary changes and increased physical activity to reduce weight, waist circumference (WC), glucose, insulin, and lipoproteins would reduce progression of subclinical atherosclerosis, carotid intimal media thickness and plaque, coronary artery calcification, and pulse wave velocity (PWV). The study focused on postmenopausal women (n = 508), mean age of 57, who were randomized to the Lifestyle Change (LC) or Health Education (HE) group. RESULTS: At 18 months of follow-up, there was significant, 17 lb, weight loss and 10 cm WC decrease in the LC group. There were significant differences in changes in low-density lipoprotein cholesterol (LDL-C), insulin, glucose, large LDL, and LDL particles between the LC and HE groups. Risk factor changes were greater for women in the LC who lost a significant amount of weight (>or=18.8 lb). Participants at 18 months were subdivided into women who had stayed on HT, 125 (28%); stopped HT after randomization, 145 (33%); and not on HT at baseline but stopped an average of 7 months prior to randomization, 173 (39%). Weight loss in the LC was similar for all three groups, but LDL lipoprotein response was better for women who stopped HT after randomization or were not on HT at baseline. CONCLUSIONS: The trial has been successful in increasing exercise and diet changes and reduction in weight and WC and variables related to metabolic syndrome.

J Womens Health (Larchmt). 2006 Oct;15(8):898-908

Estrogen and androgen hormone therapy and well-being in surgically postmenopausal women.

Kotz K, Alexander JL, Dennerstein L.

Kotz Health Policy Consulting, Orinda, California 94563, USA. krista.kotz@kp.org

BACKGROUND: Women undergoing surgical menopause experience an abrupt drop in gonadal hormones and are more likely to have symptoms that negatively impact well-being, including hot flashes, sexual dysfunction, psychological problems, and testosterone deficiency. The purpose of this review was to examine the effects of hormone therapies on well-being among surgically menopausal women. METHODS: Studies were retrieved using both Cochrane and PubMed searches. A systematic literature review was performed to identify double-blind randomized controlled trials of the effects of menopausal hormone therapies on quality of life and well-being among women who have undergone hysterectomy with bilateral oophorectomy. Two studies meeting these criteria were included for review. RESULTS: For each study reviewed, the following aspects were examined: type of hormonal therapies used, inclusion/exclusion criteria, overall changes, and changes in specific parameters of well-being. General well-being improved from baseline with certain types and doses of estrogen or estrogen plus testosterone therapy, with no serious adverse events. CONCLUSIONS: Estrogen with or without testosterone may improve general well-being in some groups of surgically menopausal women. Levels of serum estrogen achieved in these studies were within a normal range for premenopausal women. Adding testosterone to estrogen therapy may provide additional improvements in well-being in some women, but only at supraphysiological levels of total testosterone and physiological levels of free testosterone. It is recommended that the clinician discuss the potential benefits and risks with each woman and devise an individualized plan based on shared decision making.

Climacteric. 2006 Dec;9(6):464-472

Effect of different preparations of hormone therapy on sexual dysfunction in naturally postmenopausal women.

Osmanagaoglu MA, Atasaral T, Baltaci D, Bozkaya H.

Karadeniz Technical University, Faculty of Medicine, Department of Obstetrics and Gynecology, Trabzon, Turkey.

Objective To compare the effect of different formulations of continuous combined hormone therapy on sexual performance in naturally postmenopausal women.Material and methods A total of 158 postmenopausal women were enrolled and prospectively randomized to the single-blind study. Fifty-four women received tibolone 2.5 mg, 53 received 2 mg estradiol and 2 mg dienogest (E2/dienogest), and 51 did not receive any menopausal therapy. The patients were monitored after 6 months. Attitudes of sexuality were evaluated by using the Rosen's female sexual function index.Results Compared with E2/dienogest and the control group, tibolone treatment was associated with more improvement of sexual performance, including sexual desire, sexual arousal and satisfaction. Both of the hormone therapies decreased frequencies of vaginal dryness and painful intercourse.Conclusions Tibolone has more positive effects on the sexual dysfunction of postmenopausal women and may be an alternative to the E2/dienogest preparation in postmenopausal women with sexual dysfunction.

Climacteric. 2006 Dec;9(6):459-63

A study of women on long-term hormone replacement therapy and their attitude to suggested cessation.

Horner E, Fleming J, Studd J.

Academic Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London, UK.

Objective The study was undertaken to determine the effect of advice to discontinue hormone replacement therapy (HRT) on 100 women who were well established on treatment without side-effects.Method The study was retrospective from November 2003 to April 2004, in a single gynecological practice in London, UK. One hundred consecutive long-term estrogen and testosterone hormone implant users were assessed as to their knowledge of recent studies regarding risks of long-term HRT and whether they wished to discontinue hormones.Results All women receiving estrogen and testosterone implants, for a mean duration of 17.65 years (range 10-28 years), felt well informed concerning the Women's Health Initiative Study and the Million Women Study but only three women were happy to discontinue. The reasons given for the continuation of therapy were that they felt well and their quality of life had greatly improved. The mean estradiol and testosterone levels were 921 pmol/l and 1.91 nmol/l, respectively.Conclusions The high rate of continuation of hormone treatment indicates that, despite the recent adverse publicity, these women feel well informed and were not willing to discontinue with their hormone therapy if they felt well. A regular discussion of the risks and benefits of HRT remains mandatory.

Climacteric. 2006 Dec;9(6):437-45.

The long-term effects of low-dose 17beta-estradiol and dydrogesterone hormone replacement therapy on 24-h ambulatory blood pressure in hypertensive postmenopausal women: a 1-year randomized, prospective study.

Kaya C, Dincer Cengiz S, Cengiz B, Akgun G.

Department of Obstetrics and Gynecology, Guven Hospital.

Objective The aim of this study was to assess the long-term effects of low-dose oral hormone replacement therapy (HRT) on 24-h blood pressure in hypertensive postmenopausal women.Study design In this 12-month, prospective study, 66 postmenopausal women with mild or moderate hypertension were randomly assigned to receive either HRT with 1 mg/day micronized 17beta-estradiol sequentially combined with 10 mg/day dydrogesterone for 14 days of each 28-day cycle, or no therapy. Ambulatory blood pressure measurements were recorded for a 24-h period at baseline and after 12 months of treatment or follow-up.Results Blood pressure did not differ significantly between the groups at baseline. After 12 months, there were falls in 24-h systolic, diastolic and mean arterial blood pressure in both the HRT and control groups; only the fall in mean arterial blood pressure in the HRT group achieved statistical significance (-2.0 +/- 0.8 mmHg, p < 0.01). While there was no significant decrease in daytime systolic or mean arterial blood pressure in either group, a significant decrease in diastolic blood pressure (-1.8 +/- 10 mmHg, p < 0.001) was observed in the HRT group. Night-time systolic and mean arterial blood pressure also decreased significantly (p < 0.001) in the HRT group (-3.0 +/- 1.5 mmHg and -2.2 +/- 0.6 mmHg, respectively), but no significant change was observed in the control group.Conclusion Low-dose oral HRT caused significant falls in both daytime and night-time ambulatory blood pressure in postmenopausal women with mild or moderate hypertension.

Climacteric. 2006 Dec;9(6):430-6

Comparison between phytoestrogens and estradiol in the preventionof atheroma in ovariectomized cholesterol-fed rabbits.

Haines C, James A, Sahota D, Chen ZY, Panesar N, Tomlinson B, Chow L, Benzie I, Husband A.

Departments of Obstetrics and Gynaecology.

Objectives There is increasing interest in the role of complementary and alternative medicines for the treatment of menopause-related problems. This study compared the preventive effect on atheroma formation of a commercially available mixed phytoestrogen concentrate with that of estradiol.Methods An ovariectomized cholesterol-fed rabbit model of atheroma formation was used. Rabbits were ovariectomized before the commencement of the 12-week treatment period. There were two control groups. Control Group 1 received isoflavone-free rabbit chow whilst Control Group 2 received 1% cholesterol-enriched isoflavone-free rabbit chow. Rabbits in Group 3 received 1% cholesterol-enriched isoflavone-free rabbit chow plus a 500 mg tablet containing a concentrated extract of Trifolium pretense (red clover). Rabbits in Group 4 received 1% cholesterol-enriched isoflavone-free rabbit chow plus a 0.5 mg tablet of oral estradiol. Atheroma formation was measured by, first, calculation of the area of atheroma on the intimal surface, and, second, measuring the cholesterol content in the aorta.Results There were no significant differences in serum cholesterol between the cholesterol-fed control Group 2 and the treatment Groups 3 and 4. However, there was significantly less staining for atheroma and significantly less cholesterol accumulation in the aorta in Group 4 (estradiol-treated) rabbits compared with either control Group 2 or Group 3 (phytoestrogen-treated) rabbits.Conclusion In this study, only estradiol was shown to have a significant protective effect against atheroma formation.

Climacteric. 2006 Dec;9(6):416-20

Risk of cardiovascular disease in relation to the use of combined postmenopausal hormone therapy: detection bias and resolution of discrepant findings in two Women's Health Initiative studies.

Shapiro S.

Department of Family Medicine and Public Health, University of Cape Town Medical School, Cape Town, South Africa.

Context In a recent analysis of data in the Women's Health Initiative (WHI) clinical trial and observational studies, the overall risks of coronary heart disease, stroke and venous thromboembolism, in postmenopausal women who used combined therapy with conjugated estrogens and medroxyprogesterone acetate, were lower in the observational data. However, the risks became more similar within similar duration categories of follow-up. In both studies, there was initial elevation, followed by a duration-dependent reduction, in the risks. The investigators suggest that the discrepancies in the overall risks may be due to weighting by short-duration exposure in the clinical trial, and long-duration exposure in the observational study.Critique In the clinical trial, 44% of the hormone therapy recipients were unblinded, mainly because of persistent vaginal bleeding, and awareness of exposure status was therefore common; in the observational study, all exposed women were aware. When follow-up in the WHI studies commenced, extensive publicity was given to evidence to suggest that, among women who had already sustained a myocardial infarction, combined hormone therapy may not decrease the risk of a second myocardial infarct, as hypothesized, but instead increase it. From the commencement of follow-up onward, detection bias was therefore possible in both WHI studies. That possibility was further reinforced after about 3 years of follow-up, and again a year later, when the clinical trial participants were explicitly informed that supplemental hormones were associated with increased cardiovascular risks. That information was also given extensive publicity.Conclusions Detection bias could not be ruled out in either WHI study, and there may have been systematic overestimation of the risks of cardiovascular outcomes associated with the use of combined hormone therapy. To a limited extent, an analysis of the clinical trial data according to blinding status might be informative in determining whether detection bias could have given rise to overestimation of the overall and duration-specific risks in both WHI studies. If numbers permit, comparisons within strata of severity might also be informative. If the risks were overestimated in the WHI studies, a duration-related protective effect of combined hormone therapy on the risk of coronary heart disease and stroke may have gone undetected.

Climacteric. 2006 Dec;9(6):404-15

Is HRT justified for symptom management in women at higher risk of developing breast cancer?

Rippy L, Marsden J.

King's Breast Care, King's College Hospital NHS Trust, London, UK.

Hormone replacement therapy (HRT) is the most efficacious intervention for the treatment of estrogen-deficiency symptoms. Prescriptions for HRT have fallen over the last 3 years due to anxiety provoked about breast cancer risk and recurrence that has been generated by recent clinical trials. In women at population risk of breast cancer, these trials have not shown risks greater than estimates from clinical trial evidence that predated them. For women at increased breast cancer risk due to a family history or high-risk benign breast conditions, clinical trial data are limited but suggest a lack of an additive effect of HRT on risk. In symptomatic breast cancer survivors, observational data suggest no increase in recurrence but these data are open to bias. Interim analyses of large, randomized trials have shown contradictory outcomes and, as a result, three large HRT randomized trials have now been closed. The randomized LIBERATE trial evaluating tibolone in breast cancer survivors is fully recruited and continuing. The current clinical climate is 'HRT adverse' but, due to a lack of effective alternatives for symptom relief, women at higher breast cancer risk and breast cancer survivors are still requesting information about HRT. In this situation, discussion of the current clinical uncertainty surrounding the use of HRT must be undertaken to ensure that women are adequately informed.

Maturitas. 2006 Nov 1; [Epub ahead of print]

Sexual and psychological symptoms in the climacteric years.

Amore M, Di Donato P, Berti A, Palareti A, Chirico C, Papalini A, Zucchini S.

Dipartimento di Neuroscienze, Sezione di Psichiatria, Universita di Parma, Parma, Italy.

OBJECTIVES: To provide epidemiological data about psychological and sexual functioning during menopausal transition in a large Italian non-clinical sample, and to investigate their correlation with life events. METHODS: The study design was a cross-sectional postal survey of a menopausal sample of women recruited from the General Registry Office in Ferrara's province. The sample was composed of four thousand and seventy-three women; they were sent a questionnaire designed on the basis of the Women's Health Questionnaire (WHQ). Together with the WHQ, the subjects filled out a personal file to define social status, cultural level, family's characteristics, recent menstrual cycles, gynaecological history and operations, drug assumption, life events in the last year, and lifetime depression. RESULTS: One thousand three hundred and forty-five women provided usable questionnaires. Factor analysis resulted in eight clusters: somatic symptoms, depressive symptoms, depressed mood with anxiety symptoms, cognitive difficulties, anxiety, sexual functioning, vasomotor symptoms and sleep problems. Mood and sexual function were impaired through the menopausal transition, with depressive and sexual symptoms being higher in the post-menopausal group compared to the pre-menopausal one. Therefore, the correlation between the two was greater in the pre- and peri-menopausal period. CONCLUSION: Depressive and sexual symptoms presented greater severity in the post-menopausal group. Both clusters of symptoms were strongly associated with life events. The parallel course of the two clusters could be related with a common pathoplastic action of life events, both on sexual symptoms and on depressive symptoms, occurring right at the time that a woman has to face the transition into menopause.

Semana del 4 al 12 de Septiembre de 2006

Dr. Juan Enrique Blümel

Int J Clin Pract. 2006 Sep;60(9):1087-92

The evolving role of testosterone in the treatment of erectile dysfunction.

Shabsigh R, Rajfer J, Aversa A, Traish AM, Yassin A, Kalinchenko SY, Buvat J.

Department of Urology, Columbia University, New York, NY, USA.

Hypogonadism may play a significant role in the pathophysiology of erectile dysfunction (ED). A threshold level of testosterone may be necessary for normal erectile function. Testosterone replacement therapy is indicated in hypogonadal patients and is beneficial in patients with ED and hypogonadism. Monotherapy with testosterone for ED is of limited effectiveness and may be most promising in young patients with hypogonadism and without vascular risk factors for ED. A number of laboratory and human studies have shown the combination of testosterone and other ED treatments, such as phosphodiesterase type 5 (PDE5) inhibitors, to be beneficial in patients with ED and hypogonadism, who fail PDE5 inhibitor therapy alone. There is increasing evidence that combination therapy is effective in treating the symptoms of ED in patients for whom treatment failed with testosterone or PDE5 inhibitors alone. Testosterone replacement therapy has potentially evolved from a monotherapy for ED in cases of low testosterone, to a combination therapy with PDE5 inhibitors. Screening for hypogonadism may be useful in men with ED who fail prior PDE5 inhibitors, especially in populations at risk for hypogonadism such as type 2 diabetes and the metabolic syndrome.

Proc Natl Acad Sci U S A. 2006 Sep 7; [Epub ahead of print]

Progestin negatively affects hearing in aged women.

Guimaraes P, Frisina ST, Mapes F, Tadros SF, Frisina DR, Frisina RD.

Departments of Otolaryngology, University of Rochester School of Medicine and Dentistry, Rochester, NY

Female hormone influences on auditory system aging are not completely understood. Because of widespread clinical use of hormone replacement therapy (HRT), it is critical to understand HRT effects on sensory systems. The present study retrospectively analyzed and compared hearing abilities among 124 postmenopausal women taking HRT, treated with estrogen and progestin (E+P; n = 32), estrogen alone (E; n = 30), and a third [non-hormone replacement therapy (NHRT; n = 62)] control group. Subjects were 60-86 years old and were matched for age and health status. All had relatively healthy medical histories and no significant noise exposure, middle-ear problems, or major surgeries. Hearing tests included pure-tone audiometry, tympanometry, distortion-product otoacoustic emissions (DPOAEs), transient otoacoustic emissions, and the hearing-in-noise test (HINT). The HINT tests for speech perception in background noise, the major complaint of hearing-impaired persons. Pure-tone thresholds in both ears were elevated (poorer) for the E+P relative to the E and control groups. For DPOAEs, the E+P group presented with lower (worse) levels than the E and control groups, with significant differences for both ears. For the HINT results, the E+P group had poorer speech perception than the E and control groups across all background noise speaker locations and in quiet. These findings suggest that the presence of P as a component of HRT results in poorer hearing abilities in aged women taking HRT, affecting both the peripheral (ear) and central (brain) auditory systems, and it interferes with the perception of speech in background noise.

J Sex Marital Ther. 2006 Oct-Dec;32(5):369-78

The Enhancement of Female Sexual Function with ArginMax, a Nutritional Supplement, Among Women Differing in Menopausal Status.

Ito TY, Polan ML, Whipple B, Trant AS.

School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.

We conducted a double-blind, placebo-controlled study to determine the role of dietary supplementation on sexual function in women of differing menopausal status. One hundred eight (108) women, age 22-73 years, who reported a lack of sexual desire, enrolled as participants. Of these, 55 received ArginMax for women and 53 received placebo. ArginMax for women contains L-arginine, ginseng, ginkgo, damiana, multivitamins, and minerals. The 108 women, given definitions, self-reported as 59 premenopausal (PRE); 20 perimenopausal (PERI), and 29 postmenopausal (POST). After 4 weeks, PRE women on ArginMax primarily reported significant improvement in level of sexual desire (72%; p = 0.03) and satisfaction with overall sex life (68%; p = 0.007), compared with placebo group, according to the Female Sexual Function Index (FSFI; Kaplan et al., 1999) scales. Frequency of sexual desire (60%; p = 0.05) and frequency of intercourse (56% p = 0.01) also increased among the PRE women. In contrast, among PERI women, primary improvements were reported for frequency of intercourse (86%; p = 0.002), satisfaction with sexual relationship (79%; p = 0.03), and vaginal dryness (64%; p = 0.03) compared with placebo group. POST women primarily showed an increased in level of sexual desire, with 51% showing improvement, compared with only 8% in the placebo group (p = 0.008). Nutritional intervention plays an important role in women's sexual health, but issues and areas of greatest improvement differ among women of different menopausal states. The largest number of attribute improvements were seen in PRE and PERI women, although attribute types vary among these groups. Level of desire was shown to increase significantly in POST women. Since ArginMax for women has been shown to exhibit no estrogen activity, it may be desirable alternative to hormone therapy for sexual concerns.

Breast J. 2006 Sep-Oct;12(5):413-7

Follow-up recommendations for benign breast biopsies.

Shin S, Schneider HB, Cole FJ Jr, Laronga C.

Department of Surgery, Eastern Virginia Medical School, Norfolk, Virginia.

Histologically proven benign breast disease increases a woman's relative risk for subsequent cancer development. Yet follow-up guidelines for mammogram and clinical breast examination after a benign breast biopsy are lacking. Our objective was to determine if increased surveillance is indicated following a benign breast biopsy. Following institutional review board approval, a retrospective database review was conducted of prospectively gathered patients who had a benign breast biopsy (core or excisional) for an abnormality detected on mammogram, ultrasound, or clinical breast examination. Follow-up, for all subjects, was a clinical breast examination and mammogram or ultrasound at 6 months, 1 year, and 2 years after benign breast biopsy by a breast surgeon. End points were the need for additional biopsies or cancer detection. Statistical analysis was performed using chi-squared analysis. From January 2000 to July 2003, 156 patients age 18-86 years had a benign breast biopsy. During the 2 year follow-up, 20 patients (13%) required a subsequent biopsy. No significant difference was observed in mean age, race, menarche, menopause, parity, age at first live birth, use of oral contraceptives, history of prior biopsy, or the pathology of the initial lesion between those who needed a subsequent biopsy and those who did not. Seven excisional biopsies were performed (one at 6 months, four at 1 year, and two at 2 years follow-up) for growth of the benign breast biopsy lesion, and pathology remained concordant with the original diagnosis. Thirteen biopsies were done for new findings on mammogram or ultrasound. Three of these (1.9%) yielded a cancer diagnosis (one at 6 months, one at 1 year, and one at 2 years follow-up). No new lesions were identified on follow-up by clinical breast examination alone. Increased surveillance following a benign breast biopsy is necessary because of the increased need for subsequent biopsy or risk of cancer development. This should include imaging (mammography or ultrasound) and a clinical breast examination 6 months, 1 year, and 2 years after a benign breast biopsy.

Minerva Ginecol. 2006 Aug;58(4):335-44

Tibolone in the treatment of menopause: compliance, efficacy and safety in a ten year experience.

Bianco V, Murina F, Roberti P, Valente I.

Second Obstetric and Gynecological Department University of Milan, Milan, Italy.

AIM: To assess tibolone compliance, efficacy and safety in everyday clinical practice a non-randomized, prospective, cohort clinical study was carried out. METHODS: One hundred and fifty post-menopausal women aged 48 to 73 years were prescribed tibolone: 72 of them were treated for 36.4 months, 55 terminated treatment after less than 1 year, while 23 never took the tablets after seeking for menopause counseling and having agreed upon the treatment. We examined: endometrial thickness and histology, total cholesterol, triglycerides, fibrinogen, AST, ALT, gamma-gt, and the body weight. RESULTS: Side effects were the main causes of withdrawal (32%), and insufficient therapeutic effect and adverse events for a small number of cases (5.5% and 4.7% respectively), while various causes (fear of cancer, missing tablets, family doctor or other specialist's advice, remission of symptoms) were responsible for terminating treatment after extended periods. Laboratory findings showed a favorable trend; only the (GT showed slightly higher mean values, although within a normal range. On average, weight during treatment increased of 1.5 kg, and endometrial thickness grew of 1.3 mm in a mean time of 34.5 months of observation. An average of 2.3%/year increase of bone mineral density was reported, though bone mass didn't improve in some patients. CONCLUSIONS: Different causes of terminating treatment are related to the length of treatment, side effects being the main reason for early withdrawals, efficacy on symptoms or medical advice or fear of treatment for extended periods of time. Effectiveness on bone mass, safety as resulting from endometrial thickness and laboratory measures are confirmed. It is suggested to enhance follow-up accuracy and reinforce counseling as measures to improve compliance.

J Hypertens. 2006 Oct;24(10):2017-22

Type 2 diabetes mellitus is a risk factor for the development of hypertension in postmenopausal women.

Rossi R, Turco V, Origliani G, Modena MG.

Institute of Cardiology, University of Modena, Modena, Italy.

OBJECTIVE: Hypertension and type 2 diabetes mellitus are common diseases that are frequently found concomitantly in postmenopausal women. These findings suggest a close and/or synergistic nature in the relationship between the two disease processes; however, no prospective data exist on the incidence rate of hypertension in postmenopausal women with type 2 diabetes mellitus. METHODS: The present study assessed the risk of developing hypertension in 840 postmenopausal women: 102 women (12.1% of the cohort) with type 2 diabetes mellitus and 738 (87.9%) free of diabetes. The mean +/- SD follow-up was 3.2 +/- 0.9 years (range 0.5-6.0 years). RESULTS: The incidence rate (cases of hypertension per 100 person-years) was 1.1 for the group of women without diabetes versus 5.6 in women with diabetes (P < 0.0001). Compared with the non-diabetic group, women with type 2 diabetes mellitus had a statistically significant higher risk of developing hypertension. The relative risks for women with diabetes was 5.09 [crude: 95% confidence interval (CI) = 3.52-7.36; P < 0.0001]; 3.43 (adjusted for body mass index and waist circumference: 95% CI = 2.25-5.14; P < 0.001); and 2.95 (adjusted for all potential confounders: 95% CI = 1.86-4.32; P < 0.01). CONCLUSION: In our prospective study, on the incidence of hypertension, the presence of type 2 diabetes was found to be a potent independent risk determinant. This suggests that postmenopausal women affected by type 2 diabetes mellitus comprise a population at high risk for the subsequent development of hypertension.

Drugs 2006;66(12):1593-601.

Intravenous ibandronate : in the treatment of osteoporosis.

Croom KF, Scott LJ.

Adis International Limited, Auckland, New Zealand.

black triangle Ibandronate (ibandronic acid) is a potent nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption in women with postmenopausal osteoporosis. Recently, an intravenous (IV) formulation of ibandronate for intermittent injection, which circumvents the fasting and posture requirements associated with administration of oral bisphosphonates, was approved for use in this patient population.black triangle In initial placebo-controlled studies of 1 year's duration, IV ibandronate (</=2mg once every 3 months) increased lumbar spine bone mineral density (BMD) and reduced levels of biochemical markers of bone turnover in a dose-dependent manner. Dosages </=1mg every 3 months were found to be suboptimal in terms of fracture prevention in a 3-year trial.black triangle Subsequently, the large randomised, double-blind, noninferiority DIVA trial showed that, in terms of increasing lumbar spine BMD (primary endpoint), IV ibandronate 3mg once every 3 months and 2mg once every 2 months for 1 year were noninferior and also superior to oral ibandronate 2.5mg once daily, a regimen with proven antifracture efficacy. Median reductions from baseline in biochemical markers of bone turnover were similar for the IV and oral regimens.black triangle IV ibandronate was generally well tolerated in clinical trials. Treatment-related adverse events included musculoskeletal events and transient influenza-like symptoms, the latter mainly associated with the first dose.

J Natl Cancer Inst. 2006 Sep 6;98(17):1204-14

Prospective breast cancer risk prediction model for women undergoing screening mammography.

Barlow WE, White E, Ballard-Barbash R, Vacek PM, Titus-Ernstoff L, Carney PA, Tice JA, Buist DS,

Cancer Research and Biostatistics, 1730 Minor Avenue, Suite 1900, Seattle, WA 98101, USA.

BACKGROUND: Risk prediction models for breast cancer can be improved by the addition of recently identified risk factors, including breast density and use of hormone therapy. We used prospective risk information to predict a diagnosis of breast cancer in a cohort of 1 million women undergoing screening mammography. METHODS: There were 2,392,998 eligible screening mammograms from women without previously diagnosed breast cancer who had had a prior mammogram in the preceding 5 years. Within 1 year of the screening mammogram, 11,638 women were diagnosed with breast cancer. Separate logistic regression risk models were constructed for premenopausal and postmenopausal examinations by use of a stringent (P<.0001) criterion for the inclusion of risk factors. Risk models were constructed with 75% of the data and validated with the remaining 25%. Concordance of the predicted with the observed outcomes was assessed by a concordance (c) statistic after logistic regression model fit. All statistical tests were two-sided. RESULTS: Statistically significant risk factors for breast cancer diagnosis among premenopausal women included age, breast density, family history of breast cancer, and a prior breast procedure. For postmenopausal women, the statistically significant factors included age, breast density, race, ethnicity, family history of breast cancer, a prior breast procedure, body mass index, natural menopause, hormone therapy, and a prior false-positive mammogram. The model may identify high-risk women better than the Gail model, although predictive accuracy was only moderate. The c statistics were 0.631 (95% confidence interval [CI] = 0.618 to 0.644) for premenopausal women and 0.624 (95% CI = 0.619 to 0.630) for postmenopausal women. CONCLUSION: Breast density is a strong additional risk factor for breast cancer, although it is unknown whether reduction in breast density would reduce risk. Our risk model may be able to identify women at high risk for breast cancer for preventive interventions or more intensive surveillance.

J Br Menopause Soc. 2006 Sep;12(3):115-25

A 10-year follow-up of postmenopausal women on long-term continuous combined hormone replacement therapy: update of safety and quality-of-life findings.

Heikkinen J, Vaheri R, Timonen U.

The Deaconness Institute of Oulu, Isokatu, Oulu, Finland.

OBJECTIVE: To assess the safety and health-related quality of life (HRQOL) of continuous combined hormone replacement therapy (ccHRT) with estradiol valerate/medroxyprogesterone acetate (E(2)V/MPA) over nine years and at follow-up one year after discontinuation. Study design: A total of 419 women were randomized to one of four treatments: once-daily 1 mg E(2)V/2.5 mg MPA (1 + 2.5 group); 1 mg E(2)V/5 mg MPA daily (1 + 5 group); 2 mg E(2)V/2.5 mg MPA daily (2 + 2.5 group); 2 mg E(2)V/5 mg MPA daily (2 + 5 group) (Indivina, Orion Pharma). For the last six months, all received the 1 + 2.5 dosage. The 2 + 2.5 dosage was discontinued at the end of year 7. A total of 198 women continued after year 7. RESULTS: Annualized percentage rates for cardiovascular, stroke, breast and endometrial cancer events were below national rates for Finland and those reported for the Women's Health Initiative. There were no serious events with the 1 + 2.5 dosage or after ccHRT discontinuation. Climacteric symptoms remained significantly below baseline values after dosage reduction; some symptoms recurred after discontinuation of ccHRT. HRQOL ratings improved with ccHRT, irrespective of dosage, including depressed mood, anxiety, health perception and sexual interest. Scores on a scale assessing daily functioning and enjoyment (Q-LES-Q) improved from year 7 to year 9. They deteriorated during follow-up in women not continuing ccHRT. CONCLUSIONS: Lower dosages of HRT were as effective as higher doses in improving climacteric symptoms and HRQOL ratings and had fewer safety concerns. Following discontinuation of ccHRT, patient satisfaction was variable, with 15% electing to continue or restart HRT and 7% resuming at follow-up. This supports the need for an individualized approach to therapy recommendations.

J Br Menopause Soc. 2006 Sep;12(3):104-8

Migraine and the menopause.

Macgregor EA.

City of London Migraine Clinic, London, UK.

The prevalence of migraine peaks during the 40s and an increased association between migraine and menstruation is often noted. Migraine generally improves after the menopause. Although menstrual irregularity, hot flushes and other climacteric symptoms may warrant management with hormone replacement therapy (HRT), there has been some concern that HRT may aggravate migraine and potentially increase the risk of ischaemic stroke. This evidence-based review concludes that migraine is not a contraindication for HRT but continuous-release transdermal estrogen, in the lowest effective dose, is recommended.

Fertil Steril. 2006 Sep;86(3):700-10

A randomized controlled pilot study of acupuncture for postmenopausal hot flashes: effect on nocturnal hot flashes and sleep quality.

Huang MI, Nir Y, Chen B, Schnyer R, Manber R.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, Ca.

OBJECTIVE: To assess the effectiveness of acupuncture on postmenopausal nocturnal hot flashes and sleep. DESIGN: Prospective randomized placebo-controlled study. SETTING: Stanford University School of Medicine and private acupuncture offices. INTERVENTION(S): Active or placebo acupuncture was administered for nine sessions over seven weeks. MAIN OUTCOME MEASURE(S): Severity and frequency of nocturnal hot flashes from daily diaries and Pittsburgh Sleep Quality Index (PSQI). PATIENT(S): Twenty-nine postmenopausal women experiencing at least seven moderate to severe hot flashes daily, with E(2) <18 pg/mL and FSH 30.0-110.0 IU/L. RESULT(S): Nocturnal hot-flash severity significantly decreased in the active acupuncture group (28%) compared with the placebo group (6%), P=.017. The frequency of nocturnal hot flashes also decreased in the active group (47%, P=.001), though it was not significantly different from the placebo group (24%, P=.170; effect size = 0.65). Treatment did not differentially influence sleep; however, correlations between improvements in PSQI and reductions in nocturnal hot flash severity and frequency were significant (P<.026). CONCLUSION(S): Acupuncture significantly reduced the severity of nocturnal hot flashes compared with placebo. Given the strength of correlations between improvements in sleep and reductions in nocturnal hot flashes, further exploration is merited.

J Epidemiol. 2006 Sep;16(5):177-84

Relationships of Age at Menarche and Menopause, and Reproductive Year with Mortality from Cardiovascular Disease in Japanese Postmenopausal Women: The JACC Study.

Cui R, Iso H, Toyoshima H, Date C, Yamamoto A, Kikuchi S, Kondo T, Watanabe Y, Koizumi A, Inaba Y, Tamakoshi A.

Department of Public Health Medicine, University of Tsukuba.

BACKGROUND: Early menopause is associated with increased risk of coronary heart disease in Caucasian women. However, this association has not been examined in Asian women.METHODS: We conducted a 10-year cohort study of 37,965 Japanese post-menopausal women aged 40-79 years in the Japan Collaborative Cohort (JACC) Study. Causes of death were determined based on the International Classification of Disease.RESULTS: There were 487 mortality of stroke and 178 mortality of coronary heart disease. Late menarche or early menopause, or shorter duration of reproductive period was not associated with risk of mortality from coronary heart disease. However, compared with women with age at menarche </=13 years, those with age at menarche >/=17 years tended to have increased risk of mortality from stroke: the multivariable hazard ratio was 1.32 (95% confidence interval [CI]: 0.93-1.87, p = 0.10). Compared with women with age at menopause of >/=49 years, those with age at menopause of <49 years tended to have increased risk of coronary heart disease among women aged 40-64 years; the multivariable hazard ratio was 1.85 (95% CI: 0.92-3.73, p = 0.08).CONCLUSIONS: The possible association between early menopause and coronary heart disease among middle-aged women was consistent with the result of observational studies for Caucasian women, and can be explained by a protective effect of endogenous estrogen on the development of atherosclerosis.

Clin Cancer Res. 2006 Sep 1;12(17):5242-7

Effect of raloxifene on the incidence of invasive breast cancer in postmenopausal women with osteoporosis categorized by breast cancer risk.

Lippman ME, Cummings SR, Disch DP, Mershon JL, Dowsett SA, Cauley JA, Martino S.

Authors' Affiliations: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.

PURPOSE: To assess the effect of raloxifene, indicated for osteoporosis treatment and prevention, on invasive breast cancer in subgroups of postmenopausal women defined by risk factors for breast cancer. EXPERIMENTAL DESIGN: Data from the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) trial (N = 7,705) and a follow-up study, the 4-year Continuing Outcomes Relevant to Evista (CORE) trial (N = 4,011), were analyzed. Prespecified subgroups were defined by age (>/=65 versus <65 years), age at menopause (>/=49 versus <49 years), body mass index (>/=25 versus <25 kg/m(2)), family history of breast cancer (yes/no), serum estradiol level (5-10 versus <5, >10 versus <5 pmol/L), prior estrogen therapy (yes/no), and bone mass at MORE baseline, and 5-year predicted risk, assessed using the modified Gail model (>/=1.67 versus <1.67%), at CORE baseline. Time-to-first invasive breast cancer was analyzed using Cox proportional hazards models. RESULTS: In the placebo group, older age, higher estradiol level, and a family history of breast cancer were associated with an increased breast cancer risk (P < 0.05). Raloxifene therapy was associated with a reduced breast cancer risk in both women at lower and those at higher breast cancer risk. Hazard ratio point estimates were 0.11 to 0.67, corresponding to a 33% to 89% reduction in breast cancer risk with raloxifene versus placebo. The therapy by family history interaction was significant (P = 0.04). CONCLUSIONS: Raloxifene therapy was associated with a reduced risk of invasive breast cancer in postmenopausal women irrespective of the presence/absence of risk factors; its effect was greater in women with a family history of breast cancer.

Maturitas. 2006 Aug 30; [Epub ahead of print]

Advances in hormone replacement therapy with drospirenone, a unique progestogen with aldosterone receptor antagonism.

Palacios S, Foidart JM, Genazzani AR.

Instituto Palacios, Salud y Medicina de la Mujer, Madrid, Spain.

Unlike other currently available progestogens, drospirenone (DRSP) has a pharmacological profile, which closely mimics that of endogenous progesterone, most notably potent anti-aldosterone and anti-androgenic effects. Consequently, DRSP, when combined with 17beta-estradiol (E2) as hormone replacement therapy (HRT), offsets E2-related water and sodium retention by blocking the mineralocorticoid receptor. This review evaluates the potential benefits offered by DRSP as the progestin component of HRT with respect to its anti-aldosterone activity, which translates into positive effects on body weight and blood pressure in clinical trials of continuous, combined E2/DRSP in post-menopausal women. In a 1-year, large-scale, randomised, controlled trial, E2 1mg/DRSP 2mg significantly decreased mean body weight by 1.2kg versus baseline (P<0.001), whereas patients receiving E2 1mg gained weight. E2 1mg/DRSP 2mg also significantly lowered mean systolic blood pressure (SBP) by 9.0mmHg from baseline (P<0.05) versus 3.7mmHg in the E2 1mg group (P=0.220) in a sub-group of hypertensive women. In addition, E2/DRSP was not associated with hyperkalaemia (potassium >/=5.5meq/L) irrespective of concomitant use of ACE inhibitors, angiotensin II receptor antagonists or non-steroidal anti-inflammatory drugs, and co-morbid diabetes mellitus. In summary, as well as effectively treating climacteric symptoms, DRSP 2mg combined with E2 1mg has shown positive effects on body weight and blood pressure in clinical trials, most likely due to DRSP's anti-aldosterone properties. This combination may therefore offer an alternative therapeutic option with additional benefits beyond current HRT agents for symptomatic post-menopausal women.