1999 - 2000 - 2001 - 2002 - 2003

Osteoporos Int. 2003 Dec 16 [Epub ahead of print].

The effect of 1-year transdermal estrogen replacement therapy on bone mineral density and biochemical markers of bone turnover in osteopenic postmenopausal systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial.

Bhattoa HP, Bettembuk P, Balogh A, Szegedi G, Kiss E.
Regional Osteoporosis Center, Department of Obstetrics and Gynecology, Medical and Health Science Center, University of Debrecen, Nagyerdei Krt. 98, 4012, Debrecen, Hungary.

We studied the effect of 1-year transdermal estrogen replacement therapy (ERT) on bone mineral density (BMD) and biochemical markers of bone turnover in osteopenic postmenopausal systemic lupus erythematosus (SLE) patients in a randomized, double-blind, placebo-controlled trial. SLE patients were randomly allocated to treatment (estradiol; 50 microg transdermal 17beta-estradiol; n=15) or placebo ( n=17) group. Both groups received 5 mg continuous oral medroxyprogesterone acetate, 500 mg calcium and 400 IU vitamin D(3). L(1)-L(4) spine (LS), left femur and total hip BMD were measured at baseline and at 6 and 12 months. Serum osteocalcin (OC) and degradation products of C-terminal telopeptides of type-I collagen (CTx) levels were measured at baseline and 3, 6, 9, and 12 months. There was a significant difference in the percentage change of LS BMD at 6 months between the two groups (103.24+/-3.74% (estradiol group) vs 98.99+/-3.11% (placebo group); P<0.005). There was a significant decrease within the estradiol group in the CTx levels between baseline and all subsequent visits ( P<0.05). There was no significant difference in SLE disease activity index, Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) damage index and corticosteroid dose during the study period. Transdermal estradiol may prevent bone loss in postmenopausal SLE women at the lumbar spine and femur, with no increase in disease activity among postmenopausal SLE women receiving transdermal ERT. The high dropout rate (8/15) leads us to the conclusion that efficacy of HRT in a high-risk group such as SLE women can be attained only in a small number of patients, provided all inclusion/exclusion criteria are strictly adhered to.

Eur Heart J. 2003 Dec;24(24):2197-205.

Post menopausal hormone replacement therapy and risk of acute myocardial infarction - a case control study of women in the East Midlands, UK(1).

Chilvers CE, Knibb RC, Armstrong SJ, Woods KL, Logan RF.
Division of Epidemiology and Public Health and Trent Institute for Health Services Research, University of Nottingham, Nottingham, UK

Aims To examine the relationship between hormone replacement therapy (HRT) and acute myocardial infarction (AMI) adjusting for coronary risk factors and social and behavioural confounders that might indicate a healthy user effect and could account for the discrepancy between randomized and observational studies of HRT use.Methods A case-control study of 864 women aged between 35-65 suffering an AMI with two age matched community controls from the same geographical area. Information was collected by interview and from general practitioner records. Conditional logistic regression was used to calculate odds ratios (OR) adjusted for diabetes, hypertension, smoking, alcohol, social class, family history and a health conscious behaviour score.Results HRT use was recorded for 34% of non-fatal AMI cases and 39% of controls with the adjusted OR for ever-use of HRT versus never-use being 0.74 (95% CI 0.55-0.99). The pattern of risk of AMI was similar for oestrogen only and combined HRT. During the first 12 months of HRT use there was a small increase in risk of AMI with the adjusted OR being 1.14 (0.72-1.80). HRT use for 13-60 months was associated with a small reduction in AMI risk (adjusted OR 0.85, 0.55-1.29). Only HRT used for >60 months was associated with a substantial risk reduction (adjusted OR 0.42, 0.24-0.73). Data for deceased cases and controls showed a similar pattern.Conclusion HRT use whether as oestrogen only or combined hormones was only associated with a significant reduction in risk when used for greater than 60 months. These findings could reflect a dual effect of HRT on AMI risk by prothrombotic and anti-atherogenic mechanisms. Neither oestrogen only or combined HRT can be recommended for prevention of coronary artery disease.

Maturitas. 2003 Dec 10;46(4):255-62.

Influence of hormonal replacement therapy on the regional cerebral blood flow in postmenopausal women.

Slopien R, Junik R, Meczekalski B, Halerz-Nowakowska B, Maciejewska M, Warenik-Szymankiewicz A, Sowinski J.
Department of Gynecological Endocrinology, University of Medical Sciences of Poznan, Ul. Polna 33, 60-241 Poznan, Poland.

OBJECTIVES: The aim of this study was evaluation of the influence of hormonal replacement therapy (HRT) on the regional cerebral blood flow in postmenopausal women. METHODS: The study group were 20 postmenopausal women, mean age 48.7 years (S.D. +/- 4.9 years). The control group were ten regularly menstruating women, mean age 32.6 years (S.D. +/- 13.2 years). In the studied group we measured the severity of climacteric syndrome with the use of Kupperman index and serum FSH and 17beta-estradiol level with the use of radioimmunological method. Cerebral blood flow was measured at rest using Single Photon Emission Computed Tomography (SPECT). Tracer accumulation evaluation was performed in three slices defined as: cerebellar slice, thalamic slice and ventricular slice, the reference region was delineated in the cerebellum. In ten women with an impairment in the cerebral blood flow at the beginning of the study all the tests were repeated after 12 months of HRT. RESULTS: Before HRT mean value of the Kupperman index in the study group was 29.8 points (S.D. +/- 7.1 points); 17beta-estradiol 27 pg/ml (S.D. +/- 2 pg/ml); FSH 56 IU/l (S.D. +/- 49.5 IU/l); SPECT study revealed cerebral blood flow impairment in ten women. In all the studied slices cerebral blood flow was lower in the study group than in the controls. After 12 months of HRT the mean value of the Kupperman index in the study group was 13.2 points (S.D. +/- 2.1 points) (P < 0.05); 17beta-estradiol 44 pg/ml (S.D. +/- 25 pg/ml); FSH 36.4 IU/l (S.D. +/- 57.3 ng/ml); we found cerebral blood flow increase in all studied slices: right cerebellar slice: 5.2%; left cerebellar slice: 4.1%; right thalamic slice: 3.8%; left thalamic slice: 3.3%; right ventricular slice: 7.5%*; left ventricular slice: 6.7%* (* P < 0.05). CONCLUSIONS: Cerebral blood flow is lower in the postmenopausal women than in regularly menstruating women. HRT increases regional cerebral blood flow and this improvement coexists with an increase of serum 17beta-estradiol level.

Menopause. 2003 Nov-Dec;10(6):516-21.

Percutaneous 17 beta-estradiol gel for the treatment of vasomotor symptoms in postmenopausal women.

Archer DF; EstroGel Study Group.

SUMMARY: OBJECTIVE To determine the efficacy and tolerability of two strengths of percutaneous 17beta-estradiol in a hydroalcoholic gel and placebo in controlling vasomotor symptoms of menopause.DESIGN A total of 221 postmenopausal women were assigned randomly to treatment with percutaneous 17beta-estradiol gel 1.25 g (containing 0.75 mg of estradiol) or 2.5 g (containing 1.5 mg of estradiol) or placebo gel applied once daily for 12 weeks. The primary efficacy variable was the mean change from baseline in the frequency of moderate/severe hot flushes. In addition, the mean changes from baseline in the frequency and severity of all hot flushes were assessed. Safety and tolerability were evaluated from endometrial biopsy, adverse events, and laboratory tests.RESULTS A significant reduction (P < 0.05) in the mean frequency of moderate-to-severe hot flushes and mean frequency and severity of all hot flushes was observed with both 17beta-estradiol gel groups compared with placebo. The mean number of moderate-to-severe hot flushes at the end of the study with 17beta-estradiol gel 2.5 g, 17beta-estradiol gel 1.25 g, and placebo gel was 2.0, 2.8 and 5.2, respectively. The overall incidence of adverse events was not significantly different among groups, though a higher incidence of estrogen-related adverse events was reported with the 17beta-estradiol gel 2.5-g dose.CONCLUSIONS 17beta-estradiol gel was effective and well tolerated for alleviating moderate-to-severe hot flushes in postmenopausal women. Therapy may be initiated with the 1.25-g dose with an increase to the 2.5-g dose if needed.

Miller KJ.
Neuropsychiatric Institute, University of California at Los Angeles, Box 951759, Suite 88-201, Los Angeles, CA 90024, USA. kmiller@mednet.ucla.edu

The effect of estrogen on the brain and body of women is a controversial topic that has received a tremendous amount of attention in the past few years. Recent reviews have focused on hormone replacement therapy (HRT), medical risks, and effects on brain metabolism, cognition, risk of Alzheimer's disease, and mood. This article summarizes HRT and mood improvement in postmenopausal women. For nondepressed women, experimental designs provide no clear evidence for mood improvement associated with HRT, whereas observational studies are more likely to report mood improvement. There appears to be moderate evidence that HRT facilitates the improvement of clinical depression and the efficacy of antidepressants. Heterogeneity among studies makes it difficult to generalize and recommend HRT for mood improvement in postmenopausal women, but there is a clear need to examine the necessary duration of HRT for neuroprotection to decrease a woman's risk for depression, cognitive dysfunction, and development of Alzheimer's disease.

J Nutr. 2003 Nov;133(11):3598-3602.

Dietary Iron Is Associated with Bone Mineral Density in Healthy Postmenopausal Women.

Harris MM, Houtkooper LB, Stanford VA, Parkhill C, Weber JL, Flint-Wagner H, Weiss L, Going SB, Lohman TG.

Department of Physiology and. Department of Nutritional Sciences, The University of Arizona, Tucson, AZ 85721. Department of Pediatrics, Center for Applied Research and Evaluation, University of Arkansas for Medical Sciences, Little Rock, AR 72202. Department of Health and Behavior Studies, Teachers College, Columbia University, New York, NY.

Healthy nonsmoking postmenopausal women (n = 242; ages 40-66 y) were included in the Bone, Estrogen, and Strength Training (BEST) Study. Bone mineral density (BMD) was measured at five sites (lumbar spine L(2)-L(4), trochanter, femur neck, Ward's triangle and total body) using dual energy X-ray absorptiometry (DXA). Mean nutrient intakes were assessed using a 3-d diet record. Regression models were calculated using each BMD site as the dependent variable and iron as the independent variable. Covariates included in the models were years past menopause, fat-free mass, fat mass, use of hormone replacement therapy, total energy intake and dietary intake of protein and calcium. Using linear models, iron was associated with greater BMD at all sites (P </= 0.01), even after adjusting for protein and/or calcium. Increasing levels of iron intake (>20 mg) were associated with greater BMD at several bone sites among women with a mean calcium intake of 800-1200 mg/d. Elevated iron intake was not associated with greater BMD among women with higher (>1200 mg/d) or lower calcium intakes (<800 mg/d). Dietary iron may be a more important factor in bone mineralization than originally thought and, its combined effect with calcium on BMD warrants exploration in future studies.

Menopause: towards treatment; a la carte;

Bringer J, Raingeard I, Lefebvre P, Renard E.
Service des Maladies Endocriniennes, Hopital Lapeyronie CHRU Montpellier, 371, av. Doyen G. Giraud, 34000 Montpellier.

In spite of questioning and doubt arising from WHT study hormone substitution therapy (HST) has proven efficacy on climacteric symptoms and certain short-term and long-term consequences of menopause. Among 1000 women taking HST for ten years, eight supplementary cases of breast cancer and 6 fewer cases of colonic cancer are observed. No cardiovascular protection has been demonstrated. A history of coronary artery disease, vascular disease, stroke or thromboembolism are contraindications for HST. The vascular impact of estradiol administered via an extra-digestive route in women with a low vascular risk cannot be extrapolated from the HERS and WHI trials because these trials were conducted is high-risk women, using specific types of steroids given orally. Tibolone has demonstrated efficacy and in an alternative to HST after more than one year of menopause. The usefulness of phytoestrogens remains to be determined, particularly due to the wide individual variability of their effects on climacteric symptoms and the low level of proof provided by epidemiological or clinical studies conducted to study the prevention of osteoporosis and the risk of breast cancer. Most of the analyses present methodological biases. Currently, the most widely accepted notion is that there is a beneficial effect on cardiovascular risk. To date, SERMs have selective indications and cannot be prescribed for all women: raloxifen is used for the prevention and treatment of menopause-related osteoporosis. The relative risk of venous thromboembolism with SERMs (raloxifen and tamoxifen) is comparable to that observed with HST. HST or any other treatment given for menopause must be an individual decision balancing the benefits against the risks and taking into account the desires of the patient perfectly informed of the currently available evidence. Prescriptions should be part of an overall scheme including nutritional advise and physical exercise aimed at preserving quality of life and preventing age-related effects which largely depend on genetic predisposition and the psycho-affective environment.

Low-dose estrogen therapy for menopausal women: a review of efficacy and safety.

Crandall C.
Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Iris Cantor-UCLA Women's Health Center, Los Angeles, California.

BACKGROUND: Recent adverse events involving research of traditional estrogen therapy have led to interest in lower-than-standard doses of menopausal estrogen therapy. METHOD: The Medline (1966-present) database was searched for randomized controlled trials (keywords: low-dose estrogen, minimum dose AND estrogen, menopause, and osteoporosis) regarding hot flashes, endometrial hyperplasia, vaginal bleeding, breast tenderness, and bone density. Studies are only a few years in duration. RESULTS: The decrease in hot flashes with half-strength estrogens, range 60%-70%, is less than the 80%-90% reduction with standard dosing. Some low-dose preparations preserve lumbar and femoral bone density (although the degree of effect and quality of evidence vary among preparations). Bone density effects are dose dependent for conjugated equine estrogen (CEE), transdermal estradiol ethinyl (E(2)), norethindrone acetate (E(2)/NETA), oral E(2), and esterified estrogens. Bone preservation is likely to be less efficacious with low-dose estrogens than with traditional doses. Low-dose estrogen alone may not protect bone unless adequate calcium is given. Breast tenderness and skeletal effects are likely dose dependent. The longest endometrial safety data are 2-year data, reported for 5 microg/1 mg EE(2)/NETA and for 0.3 mg/day esterified estrogens. Some low-dose preparations have better vaginal bleeding profiles than do higher dose preparations. Breast tenderness is not totally averted with new lower-dose preparations. There are no fracture, breast cancer, or cardiovascular outcome data and a general lack of direct head-to-head comparisons involving low-dose preparations. CONCLUSIONS: Serious adverse effects linked with traditional doses of estrogens may not be averted with lower-dose preparations, and low-dose preparations should not yet be emphasized as being safer than traditional (e.g., 0.625 mg/day CEE doses).

Maturitas. 2003 Nov 20;46(3):207-12

Menopausal status, hormone replacement therapy use and risk of self-reported physician-diagnosed osteoarthritis in women attending menopause clinics in Italy.

Parazzini F.
Associazione Ostetrici Ginecologi Ospedalieri Italiani, via Alsamonti, Milan, Italy

OBJECTIVE: In order to offer data on the association between menopausal status, hormone replacement therapy use and risk of self-reported physician-diagnosed osteoarthritis (OA) in women around menopause, we analyzed information collected in the framework of a large epidemiological study conducted in Italy. METHODS: Since 1997, a large cross sectional study has been conducting on the characteristics of women around menopause attending a network of first level outpatients menopause clinics in Italy for general counseling about menopause or treatment of menopausal symptoms. Eligible for the study were women consecutively observed at the participating centers. Up to March 2000, a total of 42464 women (mean age 53 years) were observed. Women were asked, using the same questionnaire, about their general characteristics and habits, and if they suffer of OA diagnosed by a physician requiring medical or surgical treatment. RESULTS: A total of 12521 women reported OA. The risk of OA increased with body mass index (BMI), the odds ratio, OR, being for BMI>or equal to 27 versus <24, 1.56 (95%CI 1.47-1.64). The risk increased with a history of osteoporosis/osteopenia (OR 1.65, 95%CI 1.57-1.74) and was lower in more educated women (OR high school/university degree vs. primary school degree 0.79, 95%CI 0.75-0.84). Considering menopausal status, women in spontaneous or surgical menopause were, at increased risk of OA (OR 1.13, 95%CI 1.07-1.21, and 1.18, 95%CI 1.08-1.28, respectively, in women in surgical and spontaneous menopause). No clear relationship, however, emerged with age at menopause. Ever hormonal replacement therapy users were at decreased risk of OA, the OR being for ever users in comparison with never 0.73 (95%CI 0.69-0.78). CONCLUSION: This analysis gives some epidemiological support to the hypothesis that estrogen deficiency may increased the risk of OA.

Effects of 5 years of hormonal replacement therapy on menopausal symptoms and blood pressure-a randomised controlled study.

Vestergaard P, Hermann AP, Stilgren L, Tofteng CL, Sorensen OH, Eiken P, Nielsen SP, Mosekilde L.
Department of Endocrinology and Metabolism C, The Osteoporosis Clinic, Aarhus Amtssygehus, Aarhus University Hospital, Tage Hansens Gade 2, DK-8000 C, Aarhus, Denmark

OBJECTIVES: To study the effects of hormonal replacement on hot flushes, other symptoms linked to menopause, and blood pressure. METHODS: The study included 1006 early postmenopausal women aged 45-58 years, participating in the Danish Osteoporosis Prevention Study (DOPS) randomised to Hormonal replacement therapy (HRT) (n=502) or no HRT (n=504) in an open label trial. Symptom scores were recorded at baseline, after 6 month, 1, 2, and 5 years on a modified Greene scale (range 0-4 with 0 equalling no symptoms, and 4 maximal symptoms). RESULTS: HRT efficiently alleviated hot flushes (mean+/-S.E.M. score 0.48+/-0.04 in HRT vs. 0.83+/-0.05 in no HRT after 5 years, P<0.01 by repeated measures ANOVA), sleeping difficulties associated with hot flushes (0.21+/-0.60 vs. 0.37+/-0.86, P<0.01), vaginal dryness (0.45+/-0.04 vs. 0.73+/-0.05, P<0.01), dyspareunia (0.27+/-0.04 vs. 0.39+/-0.04, P<0.01), and libido (0.48+/-0.05 vs. 0.59+/-0.05, P=0.08). In the untreated group the occurrence of mood swings (from 0.77+/-0.05 at baseline to 0.45+/-0.04 after 5 years, 2P<0.01) and oedemas (from 0.59+/-0.04 to 0.43+/-0.04, 2P=0.02) decreased with age while the occurrence of incontinence increased (from 0.43+/-0.03 to 0.52+/-0.04, 2P<0.01). These changes were not influenced by HRT. Furthermore, HRT had no influence on presence of headache (0.54+/-0.05 vs. 0.58+/-0.05 after 5 years), voiding pattern (0.49+/-0.04 vs. 0.53+/-0.04), or blood pressure (mean systolic pressure 123+/-18 vs. 123+/-19, diastolic pressure 77+/-10 vs. 77+/-11). CONCLUSIONS: HRT is efficient in controlling hot flushes and vaginal dryness, and symptoms related to these conditions. However, no effect on blood pressure or other menopause symptoms was recorded.

1 October 2003, Volume 42, Issue 7 Pages 1238-1245

Hormone replacement therapy is associated with improved survival in women with advanced heart failure

JoAnn Lindenfeld (University of Colorado Health Sciences Center and Center for Women's Health Research, Denver, Colorado, USA), Jalal K. Ghali (Cardiac Centers of Louisiana, Shreveport, Louisiana, USA), Heidi J. Krause-Steinrauf (National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA), Steven Khan (Cedars-Sinai Medical Center, Los Angeles, California, USA), Kirkwood Adams (University of North Carolina, Chapel Hill, North Carolina, USA), Steven Goldman (Tucson SAVAHCS, Tucson, Arizona, USA), Mary Ann Peberdy (Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia, USA), Clyde Yancy (University of Texas Southwestern, Dallas, Texas, USA), Surai Thaneemit-Chen (VA Palo Alto Health Care System Cooperative Studies Program, Palo Alto, California, USA), Rhonda L. Larsen (Duke Clinical Research Institute, Durham, North Carolina, USA), James Young (Cleveland Clinic Foundation, Cleveland, Ohio, USA), Brian Lowes (University of Colorado Health Sciences Center and Center for Women's Health Research, Denver, Colorado, USA), Yves D. Rosenberg (National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA) and BEST Investigators Received: 2/5/2003. Revised: 4/9/2003. Accepted: 4/18/2003.

Abstract

Objectives: We sought to determine whether hormone replacement therapy (HRT) is associated with an improved prognosis in women with advanced heart failure (HF) and systolic dysfunction.
Background: There are about two million postmenopausal women in the U.S. with HF. However, limited data are available to assess the effects of HRT on survival in this large group of patients.
Methods: A retrospective analysis of women age 50 years and over entered into the Beta-Blocker Evaluation of Survival Trial (BEST) was conducted using Cox regression analysis comparing survival in HRT users and non-users after correcting for baseline variables known to predict survival in women with HF and systolic dysfunction.
Results: In 493 women age 50 years and older, HRT was associated with a significant reduction in mortality-21% mortality in HRT users and 34% in non-users (p = 0.025). Multivariate analysis demonstrated a hazard ratio for mortality of 0.6 (95% confidence INTERVAL = 0.36 to 0.97) (p = 0.039) for HRT users. The benefits of HRT were noted only in women with a nonischemic etiology of HF (n = 237).
Conclusions: Hormone replacement therapy is associated with a marked improvement in survival in postmenopausal women with advanced HF. A prospective, randomized trial of HRT should be performed in this large group of patients.
Article footnote
The BEST trial was sponsored by the Division of Epidemiology and Clinical Applications of the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs Cooperative Studies Program through an interagency agreement. Additional support was provided by Incara Pharmaceuticals Corporation, which also supplied bucindolol and placebo.

Elsevier Science Inc.

© 2003 American College of Cardiology Foundation

Menopause. 2003 Sep-Oct;10(5):390-8. Related Articles, Links

Transdermal testosterone therapy improves well-being, mood, and sexual function in premenopausal women.

Goldstat R, Briganti E, Tran J, Wolfe R, Davis SR.
Jean Hailes Foundation Research Unit, Clayton, Victoria, Australia; and the Department of Epidemiology and Preventive Medicine, Monash University, Central and Eastern Clinical School, Prahran, Victoria, Australia.

SUMMARY: OBJECTIVE Circulating testosterone in women declines during the late reproductive years such that otherwise healthy women in their 40s have approximately half the testosterone level as women in their 20s. Despite this, research showing the benefits of androgen replacement has been limited to the postmenopausal years. In view of the known premenopausal physiological decline in testosterone, we have evaluated the efficacy of transdermal testosterone therapy on mood, well-being, and sexual function in eugonadal, premenopausal women presenting with low libido.DESIGN Premenopausal women with low libido participated in a randomized, placebo-controlled, crossover, efficacy study of testosterone cream (10 mg/day) with two double-blind, 12-week, treatment periods separated by a single-blind, 4-week, washout period.RESULTS Thirty-four women completed the study per protocol, with 31 women (mean age 39.7 +/- 4.2 years; serum testosterone 1.07 + 0.50 nmol/L) providing complete data. Testosterone therapy resulted in statistically significant improvements in the composite scores of the Psychological General Well-Being Index [+12.9 (95% CI, +4.6 to +21.2), P = 0.003] and the Sabbatsberg Sexual Self-Rating Scale [+15.7 (95% CI, +6.5 to +25.0), P = 0.001] compared with placebo. A mean decrease in the Beck Depression Inventory score approached significance [-2.8 (95% CI, -5.7 to +0.1), P = 0.06]. Mean total testosterone levels during treatment were at the high end of the normal range, and estradiol was unchanged. No adverse effects were reported.CONCLUSIONS Testosterone therapy improves well-being, mood, and sexual function in premenopausal women with low libido and low testosterone. As a substantial number of women experience diminished sexual interest and well-being during their late reproductive years, further research is warranted to evaluate the benefits and safety of longer-term intervention.

Continuous intrauterine compared with cyclic oral progestin administration in perimenopausal HRT.

Boon J, Scholten PC, Oldenhave A, Heintz AP.
Department of Obstetrics and Gynecology, Diakonessenhuis, Bosboomstraat 1, 3582 KE, Utrecht, Netherlands

OBJECTIVES: Two hormone replacement therapy (HRT) regimens of combined oral estradiol with either continuous intrauterine or cyclic oral progestin were compared for 2 years. METHODS: 200 perimenopausal women randomly received an intrauterine system with continuous levonorgestrel release (20 microg/24 h) combined with oral estradiol (2 mg daily), or a cyclic oral regimen of norethisteroneacetate (1 mg on day 13-22) and estradiol (days 1-21; 2 mg, days 22-28; 1 mg). Efficacy on endometrial protection, vaginal bleeding patterns, blood loss and practical use were compared during 26 cycles. RESULTS: Endometrial protection was adequate in both regimens. The cyclic regimen induced a more regular bleeding pattern. The continuous local administration induced a reduction in bleeding (P=0.001) with an initial period of prolonged and frequent bleeding. 38% became ameorrhoeic. Women found both regimens acceptable. CONCLUSIONS: Continuous intrauterine Levonorgestrel administration by using an intrauterine system can well be recommended for use in combination with oestrogen replacement therapy in perimenopausal women.

Fertil Steril. 2003 Sep;80(3):536-40. Related Articles, Links

Effect of daily hormone therapy and alendronate use on bone mineral density in postmenopausal women.

Davas I, Altintas A, Yoldemir T, Varolan A, Yazgan A, Baksu B.
Second Obstetrics and Gynecology Clinic, Sisli Etfal Training and Research Hospital, Istanbul, Turkey

To evaluate the effect of daily oral and transdermal hormone therapy alone or in combination with alendronate on bone mineral density in postmenopausal women.Comparative prospective clinical study.Outpatient clinic of a training and research hospital.One hundred seventy-three consecutive postmenopausal women with no previous hormone therapy and a bone mineral density T score <-1 SD were randomly enrolled.Oral conjugated estrogen, alone or with alendronate, or transdermal estrogen, alone or with alendronate, given for 1 year. All patients also received medroxyprogesterone acetate and calcium.Bone density measurement at L2 to 4 region by dual-energy X-ray absorptiometry.At the end of 1 year, significant increase in bone density measurements were seen in all groups. Oral conjugated estrogen and transdermal estrogen have the same effect on bone mineral density loss. Hormone therapy alone stabilized the bone mineral density loss. Hormone therapy together with alendronate resulted in better values in all groups.Hormone therapy is adequate in osteopenic women. However, hormone therapy plus alendronate is advantageous in women with considerable bone mineral density loss.

Insomnia related to postmenopausal syndrome and hormone replacement therapy: sleep laboratory studies on baseline differences between patients and controls and double-blind, placebo-controlled investigations on the effects of a novel estrogen-progestogen combination (Climodien(R), Lafamme(R)) versus estrogen alone.

Saletu-Zyhlarz G, Anderer P, Gruber G, Mandl M, Gruber D, Metka M, Huber J, Oettel M, Graser T, Abu-Bakr MH, Gratzhofer E, Saletu B.
Departments of Psychiatry and Gynaecological Endocrinology, University of Vienna, Vienna, Austria, Jenapharm GmbH & Co. KG/Schering AG, Jena/Berlin, Germany and Department of Psychiatry, University of Alexandria, Alexandria, Egypt.

Differences in sleep and awakening quality between 51 insomniac postmenopausal syndrome patients and normal controls were evaluated. In a subsequent double-blind, placebo-controlled, comparative, randomized, three-arm trial (Climodien 2/3 = estradiol valerate 2 mg + the progestogen dienogest 3 mg = regimen A, estradiol valerate 2 mg = regimen EV, and placebo = regimen P), the effects of 2 months of hormone replacement therapy were investigated, followed by a 2-month open-label phase in which all patients received Climodien(R) 2/2 (EV 2 mg + dienogest 2 mg = regimen A*). Polysomnography at baseline demonstrated significantly deteriorated sleep initiation and maintenance, increased S1 and decreased S2 in patients. Subjective sleep and awakening quality, well-being, morning drive, wakefulness, memory and reaction time performance were deteriorated too. Treatment with both regimen A and regimen EV induced a moderate, although nonsignificant, improvement in the primary efficacy variable wakefulness during the total sleep period compared with baseline, while under placebo no changes occurred. Secondary efficacy variables concerning sleep initiation and maintenance, and sleep architecture showed similar findings. The apnea and apnea-hypopnea indices improved significantly under regimen A, compared with both baseline and placebo. Subjective sleep and awakening quality improved significantly after regimen A and EV compared with baseline, with the drug-induced changes being superior to those induced by placebo. In the open-label phase, subjective sleep quality improved further, significantly in the former regimen A group. Awakening quality, somatic complaints and morning thymopsyche did not yield any significant findings. Concerning morning noopsychic performance, memory improved significantly after regimen A compared with baseline, fine motor activity after regimen EV. Reaction time performance increased with all three compounds. In conclusion, Climodien significantly improved subjective sleep quality, the apnea and apnea-hypopnea indices of insomniac postmenopausal syndrome patients, while it only marginally improved variables concerning objective sleep and awakening quality.

Lancet. 2003 Aug 9;362(9382):419-27. Related Articles, Links

Breast cancer and hormone-replacement therapy in the Million Women Study.

Beral V; Million Women Study Collaborators.
Cancer Research UK Epidemiology Unit, Gibson Building, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK.

BACKGROUND: Current use of hormone-replacement therapy (HRT) increases the incidence of breast cancer. The Million Women Study was set up to investigate the effects of specific types of HRT on incident and fatal breast cancer. METHODS: 1084110 UK women aged 50-64 years were recruited into the Million Women Study between 1996 and 2001, provided information about their use of HRT and other personal details, and were followed up for cancer incidence and death. FINDINGS: Half the women had used HRT; 9364 incident invasive breast cancers and 637 breast cancer deaths were registered after an average of 2.6 and 4.1 years of follow-up, respectively. Current users of HRT at recruitment were more likely than never users to develop breast cancer (adjusted relative risk 1.66 [95% CI 1.58-1.75], p<0.0001) and die from it (1.22 [1.00-1.48], p=0.05). Past users of HRT were, however, not at an increased risk of incident or fatal disease (1.01 [0.94-1.09] and 1.05 [0.82-1.34], respectively). Incidence was significantly increased for current users of preparations containing oestrogen only (1.30 [1.21-1.40], p<0.0001), oestrogen-progestagen (2.00 [1.88-2.12], p<0.0001), and tibolone (1.45 [1.25-1.68], p<0.0001), but the magnitude of the associated risk was substantially greater for oestrogen-progestagen than for other types of HRT (p<0.0001). Results varied little between specific oestrogens and progestagens or their doses; or between continuous and sequential regimens. The relative risks were significantly increased separately for oral, transdermal, and implanted oestrogen-only formulations (1.32 [1.21-1.45]; 1.24 [1.11-1.39]; and 1.65 [1.26-2.16], respectively; all p<0.0001). In current users of each type of HRT the risk of breast cancer increased with increasing total duration of use. 10 years' use of HRT is estimated to result in five (95% CI 3-7) additional breast cancers per 1000 users of oestrogen-only preparations and 19 (15-23) additional cancers per 1000 users of oestrogen-progestagen combinations. Use of HRT by women aged 50-64 years in the UK over the past decade has resulted in an estimated 20000 extra breast cancers, 15000 associated with oestrogen-progestagen; the extra deaths cannot yet be reliably estimated. INTERPRETATION: Current use of HRT is associated with an increased risk of incident and fatal breast cancer; the effect is substantially greater for oestrogen-progestagen combinations than for other types of HRT.

Combination Therapy With Hormone Replacement and Alendronate for Prevention of Bone Loss in Elderly Women

A Randomized Controlled Trial

Susan L. Greenspan, MD; Neil M. Resnick, MD; Robert A. Parker, ScD
JAMA. 2003;289:2525-2533.

Context Therapy with individual antiresorptive agents has been shown to be effective for prevention and treatment of postmenopausal osteoporosis, but whether combination antiresorptive therapy with hormones and bisphosphonates is safe or efficacious or how these agents compare in elderly women is unknown.
Objective To determine whether hormone replacement and the bisphosphonate alendronate sodium in combination are efficacious and safe, and how they compare with monotherapy in community-dwelling elderly women.
Design Randomized, double-blind, placebo-controlled, clinical trial.
Setting and Participants Five hundred seventy-three community-dwelling women age 65 years or older were screened: 485 completed screening and 373 (aged 65 to 90 years) were randomized following a 3-month, open-label, run-in phase with hormone replacement and alendronate placebo. The trial was conducted at a single academic US medical center from January 1996 to May 2001.
Interventions Participants were randomly assigned in a 2 x 2 factorial design to receive hormone replacement (conjugated equine estrogen, 0.625 mg/d, with or without medroxyprogesterone, 2.5 mg/d) and alendronate, 10 mg daily, both agents, or neither. All participants received calcium and vitamin D supplements.
Main Outcome Measures Annualized change in bone mineral density of the hip and spine and occurrence of adverse events.
Results Bone mineral density at 3 years was significantly greater at all femoral and vertebral sites in women treated with combination therapy than with monotherapy, with mean (SD) increases of 5.9% (3.8) at the total hip, 10.4% (5.4) at the posteroanterior lumbar spine, and 11.8% (6.8) at the lateral lumbar spine. Mean (SD) increases in bone mass at the hip in women treated with alendronate alone were significantly greater than in those treated with hormone replacement therapy alone (4.2% [3.8] vs 3.0% [4.9]; P<.05, respectively), and alendronate resulted in more responders to therapy. All therapies were well tolerated and participant retention was 90% at 3 years.
Conclusions Combination therapy with hormone replacement and alendronate was efficacious and well tolerated in this cohort. Alendronate was superior to hormone replacement, and combination therapy was superior to either therapy alone. Combination therapy may represent an option for women with more severe disease or for those who have failed to achieve an adequate response to monotherapy.

Author Affiliations: Division of Endocrinology and Metabolism (Dr Greenspan) and Division of Geriatric Medicine (Drs Greenspan and Resnick), University of Pittsburgh Medical Center, Pittsburgh, Pa; and Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Mass (Dr Parker).

Ultralow-Dose Micronized 17 -Estradiol and Bone Density and Bone Metabolism in Older Women

A Randomized Controlled Trial

Karen M. Prestwood, MD; Anne M. Kenny, MD; Alison Kleppinger, MS; Martin Kulldorff, PhD
JAMA. 2003;290:1042-1048.

Context Estrogen therapy is known to prevent osteoporosis, but studies have shown that conventional doses increase adverse events. Whether lower doses, one quarter of standard treatment, prevent bone loss is not known.
Objective To examine the effect of 3 years of treatment with 0.25 mg/d of micronized 17 -estradiol on bone mineral density (BMD) and bone turnover in healthy older postmenopausal women.
Design, Setting, and Participants Randomized, double-blind, placebo-controlled trial conducted from July 24, 1998, through June 14, 2002, at a university general clinical research center in the United States. Healthy, community-dwelling women (N = 167) who were older than 65 years at enrollment.
Intervention Dosage of 0.25 mg/d of micronized 17 -estradiol (n = 83) or placebo (n = 84); all women who had not had a hysterectomy received 100 mg/d of oral micronized progesterone for 2-week periods every 6 months.
Main Outcome Measures The BMD of the hip, spine, wrist, and total body measured annually for 3 years. Serum and urine biochemical markers of bone resorption and formation and sex hormones were measured at baseline, 3 months, and during years 1 and 3 of treatment.
Results Mean BMD increased at all sites for participants taking low-dose estrogen (17 -estradiol) compared with placebo (P<.001). Compared with participants receiving placebo, participants taking low-dose estrogen had BMD increases of 2.6% for the femoral neck; 3.6%, total hip; 2.8%, spine; and 1.2%, total body. Markers of bone turnover, N-telopeptides of type 1 collagen, and bone alkaline phosphatase decreased significantly (P<.001) in participants taking low-dose estrogen compared with placebo. Estradiol, estrone, and sex hormone-binding globulin levels increased in the estrogen-treated group compared with placebo. The adverse effect profile was similar; specifically, there were no statistically significant differences in breast tenderness, changes in endometrial thickness or pathological effects, or annual mammographic results between the 2 groups. The number of abnormal mammograms over 3 years was 15 for the low-dose estrogen group and 10 for the placebo group (8 occurred at baseline) (P = .26). There were no reports of breast cancer during the study.
Conclusions In older women, a dosage of 0.25 mg/d of 17 -estradiol increased bone density of the hip, spine, and total body, and reduced bone turnover, with minimal adverse effects. Future studies evaluating the effect of low-dose estrogen on fractures are indicated.

Author Affiliations: Center on Aging (Drs Prestwood and Kenny and Ms Kleppinger), and Department of Community Medicine, Division of Biostatistics (Dr Kulldorff), University of Connecticut Health Center, Farmington.

Effect of tibolone on breast symptoms resulting from postmenopausal hormone replacement therapy.

Palomba S, Di Carlo C, Morelli M, Russo T, Noia R, Nappi C, Mastrantonio P, Zullo F.
Chair of Obstetrics and Gynaecology, University "Magna Graecia" of Catanzaro, Catanzaro, Via Nicolardi 188, 80131, Naples, Italy

OBJECTIVE: To evaluate the incidence of breast symptoms in a population treated with various hormone replacement therapy (HRT) regimens and to detect the variations in breast symptomatology after HRT changing to tibolone administration. METHODS: This prospective placebo-controlled clinical trial was conducted on healthy women on HRT reporting breast symptoms. A questionnaire was given to each woman to detect breast symptomatology. Breast tenderness and mastalgia were evaluated using a visual analogue scale (VAS). According to the choice of the each woman with breast symptoms, the HRT was changed to tibolone (2.5 mg/day per os) or to calcium carbonate (1 tab/day, placebo group). The duration of treatment was of 12 months. After 6 and 12 months breast symptomatology was re-evaluated. RESULTS: Among the 600 screened women, 64 (10.7%) were suffering from breast symptomatology. After 6 and 12 months of treatment with tibolone or placebo, mean VAS score for breast tenderness and for mastalgia resulted significantly (P<0.05) decreased, without differences between groups, in comparison with basal value. Only one woman had no improvement from the breast symptoms with tibolone administration. CONCLUSIONS: Shifting from classical HRT to tibolone is followed by a significant reduction of breast symptomatology in postmenopausal women with breast complaints similar to that obtained with treatment withdrawal.

A prospective, randomized, placebo-controlled study of the dose effect of oral estradiol on bone mineral density in postmenopausal Chinese women.

Haines CJ, Yim SF, Chung TK, Lam CW, Lau EW, Ng MH, Chin R, Lee DT.
Department of Obstetrics and Gynecology, The Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

OBJECTIVES: One of the long-term consequences of estrogen deficiency in postmenopausal women is an increased risk of osteoporosis. Fractures of the hip and lumbar spine are associated with considerable morbidity and mortality. Estrogen replacement therapy reduces the risk of osteoporosis, but there is no clear agreement on the most appropriate doses to be used. The aim of this study was to compare changes in bone mineral density (BMD) measurements using conventional and lower dose estradiol. METHODS: A prospective, randomized, placebo-controlled 12-month study of the effect of 1 and 2 mg estradiol on BMD in 152 hysterectomized postmenopausal Chinese women with no contraindication to the use of estrogen replacement therapy. RESULTS: Over 12 months, spinal BMD in placebo treated patients decreased by a mean of 2% from baseline (-0.02+/-0.03 g/cm(2)) while it increased by 2% in the 1 mg (0.02+/-0.03 g/cm(2)) and 3% in the 2 mg group (0.03+/-0.03 g/cm(2)). Mean changes in BMD over 12 months in the hip were -0.02+/-0.02 g/cm(2) (-2%), 0.01+/-0.02 g/cm(2) (+1%) and 0.01+/-0.03 g/cm(2) (+1%) in the placebo, 1 and 2 mg estradiol groups, respectively (P<0.05). Relative to placebo, increases in BMD in both 1 and 2 mg groups were statistically significant for both spine and hip (P<0.05). However, there was no significant difference in the increase in BMD between the 1 and 2 mg doses for either lumbar spine or hip (P=0.82, 0.53, respectively). CONCLUSION: The results of our study show that a 1 mg dose of oral estradiol is effective in preventing bone loss in postmenopausal Chinese women.

Isoflavones and cognitive function in older women: the SOy and Postmenopausal Health In Aging (SOPHIA) Study.

Kritz-Silverstein D, Von Muhlen D, Barrett-Connor E, Bressel MA.

OBJECTIVEThis study examines the effects of a dietary supplement of isoflavones on cognitive function in postmenopausal women.DESIGNParticipants for this 6-month, double-blind, randomized, placebo-controlled clinical trial were women who were in good health, were postmenopausal at least 2 years, and were not using estrogen replacement therapy. Between July 24, 2000, and October 31, 2000, 56 women aged 55 to 74 years were randomized; 2 in the placebo group and 1 in the active treatment group did not complete the 6-month evaluation, and none withdrew because of adverse effects. Women randomized to active treatment (n = 27) took two pills per day, each containing 55 mg of soy-extracted isoflavones (110 mg total isoflavones per day; Healthy Woman: Soy Menopause Supplement, Personal Products Company, McNeil-PPC Inc., Skillman, NJ, USA). Women assigned to placebo (n = 26) took two identical-appearing pills per day containing inert ingredients. Cognitive function tests administered at baseline and follow-up included the following: Trails A and B, category fluency, and logical memory and recall (a paragraph recall test assessing immediate and delayed verbal memory).RESULTSAt baseline, all women were cognitively intact; there were no significant differences by treatment assignment in age, education, depressed mood, or cognitive function (all P values > 0.10). Compliance was 98% and 97%, respectively, in the placebo and treatment groups; all women took at least 85% of their pills. The women in the treatment group did consistently better, both as compared with their own baseline scores and as compared with the placebo group responses at 6 months. Comparisons of percentage change in cognitive function between baseline and follow-up showed greater improvement in category fluency for women on active treatment as compared with the case of those on placebo (P = 0.02) and showed (nonsignificantly) greater improvement on the two other tests of verbal memory and Trails B.CONCLUSIONThese results suggest that isoflavone supplementation has a favorable effect on cognitive function, particularly verbal memory, in postmenopausal women.

Menopause. 2003 May-Jun;10(3):235-40. Related Articles, Links

Influences of hormone replacement therapy on postmenopausal women's health perceptions.

Blumel JE, Castelo-Branco C, Kerrigan N, Cancelo MJ, Blumel B, Haya J, Flores M, Carvajal MC, Sarra S.
Fundacion PROSAM, Hospital Barros Luco-Trudeau, Departmento Medicina Sur. Facultad Medicina, Universidad de Chile, Santiago, Chile.

OBJECTIVE: To assess the beliefs of climacteric women regarding their health, menopause, and hormone replacement therapy (HRT). DESIGN: Medical students asked to interview 526 healthy women, ranging from 40 to 64 years of age, between January and February of 2002. Of that number, 26 (4.9%) declined to participate in the interview. Thus, 500 women were interviewed about their beliefs and perceptions regarding their quality of life and health risks, as well as their opinions on menopause and HRT. RESULTS: The mean age of the sample was 53.3 +/- 6.2 years; 83.4% were postmenopausal, and 18.8% were HRT users. Of the women interviewed, 38.6% believed that their health was good. Although 78.8% thought that cancer is the main cause of death, 64% of them considered themselves to be at high risk for cardiovascular disease and osteoporosis. Most (64%) believed that menopause deteriorates the quality of life and that it increases cardiovascular risk (52.4%) and osteoporosis (72.0%). The HRT users perceived that they had better health status (48.9% v 36.2%, P < 0.02) and smaller cardiovascular risk (54.3% v 66.3%, P < 0.04) than did the nonusers; however, they ignored the preventive effect of estrogens in osteoporosis. CONCLUSIONS: Women believe that menopause deteriorates their health. The HRT users perceived themselves to be healthier and to have a smaller risk for cardiovascular disease.

Clin Pharmacokinet 2003;42(4):361-72 Related Articles, Links

Pharmacokinetics of selective estrogen receptor modulators.

Morello KC, Wurz GT, DeGregorio MW.
Department of Internal Medicine, Division of Hematology/Oncology, Cancer Center, University of California, Davis, Sacramento, California, USA.

Selective estrogen receptor modulators (SERMs) are a class of compounds used to treat and prevent breast cancer and osteoporosis. SERMs currently approved for use in patients include tamoxifen, toremifene and raloxifene. These compounds are well tolerated in patients, and the most common adverse effects experienced in patients undergoing SERM therapy include vasomotor symptoms such as hot flashes and vaginal discharge. New SERMs currently under development for use in the treatment and prevention of osteoporosis and breast cancer include ospemifene, a derivative of toremifene, and arzoxifene, a compound very similar in structure to raloxifene. SERMs are administered orally at doses ranging from 20 to 60 mg/day. Tamoxifen and toremifene have a bioavailability of approximately 100%, whereas that of raloxifene is only 2%. SERMs are very highly bound to plasma proteins (>95%). Tamoxifen and toremifene are metabolised by the cytochrome P450 enzyme system, and raloxifene is metabolised by glucuronide conjugation. The terminal elimination half-lives of these drugs range from 27.7 hours to 7 days. The pharmacokinetics of these compounds are affected in hepatically impaired patients, but not in renally impaired patients. SERMs have several potential drug interactions with other agents, such as warfarin, rifampicin (rifampin), cholestyramine and aromatase inhibitors.

Menopause 2003 Mar;10(2):113-132 Related Articles, Links

Role of progestogen in hormone therapy for postmenopausal women: position statement of The North American Menopause Society.

The North American Menopause Society.

OBJECTIVE To create an evidence-based position statement regarding the role of progestogen in postmenopausal hormone therapy (estrogen plus a progestogen, or EPT) for the management of menopause-related symptoms.DESIGN NAMS followed the general principles established for evidence-based guidelines to create this document. Clinicians and researchers acknowledged to be experts in the field of postmenopausal hormone therapy were enlisted to review the evidence obtained from the medical literature and develop a position statement for approval by the NAMS Board of Trustees.RESULTS The primary role of progestogen in postmenopausal hormone therapy is endometrial protection. Unopposed estrogen therapy (ET) is associated with a significantly increased risk of endometrial hyperplasia and adenocarcinoma. Adding the appropriate dose and duration of progestogen to ET has been shown to lower that risk to the level found in never-users of ET. The clinical goal of progestogen in EPT is to provide endometrial protection while maintaining estrogen benefits and minimizing progestogen-induced side effects, particularly uterine bleeding. EPT discontinuance correlates with uterine bleeding-women with more days of amenorrhea have higher rates of continuance. All US Food and Drug Administration-approved progestogen formulations will provide endometrial protection if the dose and duration are adequate. Progestogens may diminish the beneficial effects of ET on cardiovascular risk factors. However, no EPT (or ET) regimen should be initiated for the primary or secondary prevention of cardiovascular heart disease. Some progestogens may negatively affect mood. Adding progestogen to ET does not decrease the breast cancer risk, although it does not seem to increase mortality. Progestogen increases mammographic density, which is reversed after discontinuation of use. Progestogen has limited effect on the bone-enhancing action of ET. In general, the side effects of added progestogen are mild, although they may be severe in a small percentage of women.CONCLUSIONS Progestogen should be added to ET for all postmenopausal women with an intact uterus to prevent the elevated risk of estrogen-induced endometrial hyperplasia and adenocarcinoma. There is no consensus on a preferred regimen for all women. By changing the progestogen type, route, or regimen, clinicians can individualize therapy to minimize side effects, especially uterine bleeding, and limit any effects on ET benefits while providing adequate endometrial protection.

Maturitas 2003 Mar 14;44 Suppl 1:S67-77 Related Articles, Links

The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers.

Wuttke W, Seidlova-Wuttke D, Gorkow C.
Department of Clinical and Experimental Endocrinology, University of Gottingen, Robert-Koch-Strasse 40, 37075, Gottingen, Germany

OBJECTIVES: In the present study, therapeutic effects of the Cimicifuga racemosa preparation CR BNO 1055 (Klimadynon(R)/Menofem(R)) on climacteric complaints, bone metabolism and endometrium will be compared with those of conjugated estrogens (CE) and placebo. The question whether CR BNO 1055 contains substances with selective estrogen receptor modulator (SERM) activity will be investigated. METHODS: Sixty-two evaluable postmenopausal women were included in the double-blind, randomized, multicentre study, and treated either with CR BNO 1055 (daily dose corresponding to 40 mg herbal drug), 0.6 mg CE, or matching placebo, for 3 months. Menopausal symptoms were assessed by the menopause rating scale (MRS) and a diary. Levels of CrossLaps (marker of bone degradation) were determined by ELECSYS system and bone-specific alkaline phosphatase (marker of bone formation) by an enzymatic assay. Endometrial thickness was measured via transvaginal ultrasound; vaginal cytology was also studied. The primary efficacy criterion was the change from baseline to end point in the MRS. Change from baseline was analyzed for the secondary variables too. RESULTS: CR BNO 1055 proved to be equipotent to CE and superior to placebo in reducing climacteric complaints. Under both verum preparations, beneficial effects on bone metabolism have been observed in the serum. CR BNO 1055 had no effect on endometrial thickness, which was significantly increased by CE. Vaginal superficial cells were increased under CE and CR BNO 1055 treatment. CONCLUSION: The results concerning climacteric complaints and on bone metabolism indicate an equipotent effect of CR BNO 1055 in comparison to 0.6 mg CE per day. It is proposed that CR BNO 1055 contains substances with SERM activity, i.e. with desired effects in the brain/hypothalamus, in the bone and in the vagina, but without exerting uterotrophic effects.

1: Obstet Gynecol 2003 Feb;101(2):346-52 Related Articles, Links

Effect of raloxifene on the response to conjugated estrogen vaginal cream or nonhormonal moisturizers in postmenopausal vaginal atrophy.

Parsons A, Merritt D, Rosen A, Heath H, Siddhanti S, Plouffe L.
University of South Florida, Tampa, Florida, USA

To study the effect of raloxifene on the response to conjugated estrogen cream or nonhormonal moisturizer in postmenopausal women with preexisting signs of vaginal atrophy.Postmenopausal women with preexisting and untreated vaginal atrophy were enrolled in this parallel, placebo-controlled, randomized study. A total of 187 women were randomized to four treatment groups: daily oral raloxifene (60 mg per day) or a placebo in a double-blind manner plus one application of conjugated estrogen cream (0.5 g) or one applicator full of nonhormonal moisturizer, open label. The conjugated estrogen cream or nonhormonal moisturizer was applied daily for the first 2 weeks, and then twice weekly thereafter for 3 months. Efficacy of treatment regimens on signs and symptoms of vaginal atrophy was evaluated by monitoring objective and subjective parameters.Signs and symptoms of vaginal atrophy improved in all four treatment groups. Raloxifene did not diminish the magnitude of improvement when administered with either vaginal preparation. Conjugated estrogen cream produced a statistically greater improvement in signs (P <.05) but not in individual symptoms or overall satisfaction relative to nonhormonal moisturizer.Postmenopausal women with evidence of preexisting vaginal atrophy may use either low-dose conjugated estrogen cream or nonhormonal moisturizer to treat the atrophy concurrently with raloxifene (60 mg per day).

Med Lett Drugs Ther 2003 Feb 3;45(1149):9-10 Related Articles, Links

Teriparatide (Forteo) for Osteoporsis.

Teriparatide (Forteo), a recombinant segment of human parathyroid hormone, has been approved by the FDA for parenteral treatment of osteoporosis in postmenopausal women, and in men with idiopathic or hypogonadal osteoporosis, who are at high risk for fracture. Teriparatide is the first approved treatment for osteoporosis that stimulates bone formation. Other drugs approved for this indication inhibit bone resorption (Treatment Guidelines from The Medical Letter 2002; 1:13). This review describes pharmacology of the new drug. Published clinical trials are presented, along with a description of adverse effects, dosage and cost. The review also includes a comparison chart of the costs and dosages of drugs used for treatment of osteoporosis. The article concludes with an overall assessment of teriparatide's safety, efficacy and cost.

1: Ann Intern Med 2003 Jan 7;138(1):1-9 Related Articles, Links

Comment in:
Ann Intern Med. 2003 Jan 7;138(1):69-70.

Summary for patients in:
Ann Intern Med. 2003 Jan 7;138(1):I10.
Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/progestin Replacement Study. A randomized, double-blind, placebo-controlled trial.

Kanaya AM, Herrington D, Vittinghoff E, Lin F, Grady D, Bittner V, Cauley JA, Barrett-Connor E; Heart and Estrogen/progestin Replacement Study.
Division of General Internal Medicine, University of California, San Francisco, 1701 Divisadero Street, Suite 536, San Francisco, CA 94143-1732, USA. alkak@itsa.ucsf.edu

BACKGROUND: Randomized trials of postmenopausal hormone therapy have found differing effects on fasting glucose levels. No trial has evaluated the effect of hormone therapy on diabetes incidence. OBJECTIVE: To evaluate the effect of hormone therapy on fasting glucose level and incident diabetes. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: 20 U.S. clinical centers. PARTICIPANTS: 2763 postmenopausal women with coronary heart disease who were followed for 4.1 years. At baseline, 734 women had diabetes, 218 women had impaired fasting glucose, and 1811 women were normoglycemic; the 2029 women without diabetes were followed for incident diabetes. INTERVENTION: 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate daily, or placebo. MEASUREMENTS: Fasting glucose level was measured at baseline, at year 1, and at the end of the trial. Incident diabetes was defined by self-report of diabetes or disease complication, fasting glucose level of 6.9 mmol/L or greater (> or =126 mg/dL), or initiation of therapy with diabetes medication. RESULTS: Fasting glucose levels increased significantly among women assigned to placebo but did not change among women receiving hormone therapy. The incidence of diabetes was 6.2% in the hormone therapy group and 9.5% in the placebo group (relative hazard, 0.65 [95% CI, 0.48 to 0.89]; P = 0.006). The number needed to treat for benefit to prevent one case of diabetes was 30 (CI, 18 to 103). Changes in weight and waist circumference did not mediate this effect. CONCLUSIONS: In women with coronary disease, hormone therapy reduced the incidence of diabetes by 35%. This observation provides important insights into the metabolic effects of postmenopausal hormones but is insufficient to recommend the use of hormones for secondary prevention of heart disease.

Publication Types:
Clinical Trial
Randomized Controlled Trial

Minerva Med 2002 Dec;93(6):471-8 Related Articles, Links

Effects of the combined raloxifene-sodium fluoride therapy on bone mass and bone turnover in women with postmenopausal osteoporosis
[Article in Italian]

Celi M, Letizia C, Ragno A, Minisola S, D'Erasmo E, Mazzuoli GF.
Cattedra di Medicina Interna, Dipartimento di Scienze Cliniche, Policlinico Umberto I, Universita degli Studi di Roma La Sapienza, Rome, Italy.

BACKGROUND: Aim of the study was to compare the effects of raloxifene (RLX) therapy alone or with a combination of RLX and slow release sodium fluoride (SRNaF) on bone mineral density (BMD) and bone turnover, at 1 year. METHODS: Ninety-two consecutive postmenopausal women with osteoporosis (49-62 yr old) were randomly allocated to a group A (n=48; RLX 60 mg/day per os) or a group B (n=44; RLX 60 mg/day per os plus SRNaF 25 mg x 2/day per os); all participants received oral calcium carbonate (500 mg x 2/day) and vitamin D3 (400 UI x 2/day) too. Lumbar spine (L1-L4) and femoral neck (FN) BMD were measured by dual energy X-ray absorptiometry (DEXA) at time 0 (T0), after 6 (T6) and 12 (T12) months; at the same time, serum bone specific alkaline phosphatase (BALP) and urinary N-terminal telopeptide of type I collagen normalized by creatinine (NTx/cr) were determined at T0, T6 and T12. RESULTS: Eighty-five women completed the study, 45 in group A and 40 in group B. In group B, after 1 year of treatment, we found a significant (p<0.01) increase in L1-L4 BMD (3.9+/-0.3%) respect to group A (2.8+/-0.1%); FN BMD in group B increased by 3.3+/-0.3% which was significantly different (p<0.01) from group A (2.3+/-0.1%), at 1 year. After 12 months of therapy, NTx/cr decreased significantly more (p<0.05) in group B (-36+/-2.6%) than group A (-29+/-2.0%); BALP levels increased in group B and decreased in group A: in group B BALP levels (11+/-1.2%) significantly increased (p<0.001) than group A (-2.1+/-0.1%), since 6th month. CONCLUSIONS: These data demonstrate that the combination of antiresorptive and bone-stimulating agents may dissociate bone resorption and bone formation and thus, by synergestic effect, induce a significative increase in BMD.

Last Updated: 2002-09-12 16:01:46 -0400 (Reuters Health)

The effect of raloxifene, a selective estrogen receptor modulator recently approved as a therapeutic agent for menopause, on glyco-insulinemic metabolism was investigated in 40 healthy postmenopausal women. At the baseline and after 12 wk of raloxifene (60 mg/d) or placebo administration, all aspects of glucose metabolism were evaluated in each subject using both an oral glucose tolerance test (OGTT; 75 g) and a hyperinsulinemic euglycemic clamp to assess peripheral insulin sensitivity. Glucose, insulin, and C-peptide, measured in fasting conditions, as well as glucose and insulin responses to OGTT [expressed as area under curve (AUC)] were not modified by raloxifene, whereas C-peptide-AUC increased significantly (P < 0.05). Furthermore, a trend toward an improvement of peripheral insulin sensitivity and hepatic clearance of the hormone (fractional hepatic insulin extraction) was observed in the raloxifene-treated women with respect to the control patients. When the subjects were studied in relation to their insulin secretion in response to the glucose load, the patients, classified as hyperinsulinemic, showed the most significant response to the raloxifene treatment. In these women, the selective estrogen receptor modulator was able to induce a significant reduction of insulin circulating plasma values (P < 0.01) through both an increase of fractional hepatic insulin extraction (P < 0.01) and an improvement of the peripheral insulin sensitivity (P < 0.05). On the contrary, no net change of insulin dynamics was observed in normoinsulinemic and placebo-treated women. The present data indicate that raloxifene does not negatively influence glyco-insulinemic metabolism in unselected postmenopausal women and may indeed improve the excessive insulin responsiveness to OGTT in a selected population of hyperinsulinemic postmenopausal women.

Menopause 2002 Sep-Oct;9(5):329-34 Related Articles, Links

Effects of a standardized soy extract on hot flushes: a multicenter, double-blind, randomized, placebo-controlled study.

Faure ED, Chantre P, Mares P.

Department of Gynecology, Hospital Edouard Herriot, Lyon, France; Arkopharma Laboratories, Carros, France; and the Department of Gynecology, Hospital Caremeau, Nimes, France.

OBJECTIVE To investigate the effect of an oral soy isoflavone extract (Phytosoya) on hot flushes in menopausal women.DESIGN The study was conducted on outpatients according to a multicenter, randomized, double-blind, placebo-controlled, parallel-group design. A total of 75 patients in natural or surgical menopause suffering from at least seven hot flushes per day were randomized to receive during 4 months either soy isoflavone extract (total of 70 mg genistin and daidzin per day) or placebo.RESULTS There is evidence to suggest that 16 weeks of treatment with soy extract can help reduce the mean number of hot flushes per 24 hours in menopausal women. Withdrawals during this trial made it difficult to obtain an unbiased estimate of the true treatment effect, but numerous sensitivity analyses lend support to the suggestion that taking soy extract can be beneficial in the treatment of hot flushes. In particular, women taking soy extract had a 38% reduction in the mean number of hot flushes by week 4 and a 51% reduction by week 8. By the end of week 16, patients taking soy extract had a 61% reduction in their daily hot flushes versus a 21% reduction obtained with the placebo. "Responders" (defined as patients whose hot flushes were reduced by at least 50% at the end of treatment period) were 65.8% in the soy extract group and 34.2% in the placebo group ( < 0.005).CONCLUSION Soy isoflavone extract may help to reduce the frequency of hot flushes in climacteric women and provides an attractive addition to the choices available for relief of hot flushes.

Geriatrics 2002 Aug;57(8):18-20, 23-4 Related Articles, Links

Hormone replacement therapy. An analysis of efficacy based on evidence.

Gupta G, Aronow WS.

Department of Medicine, Geriatrics Division, New York Medical College, Valhalla, NY, USA.

Hormone replacement therapy (HRT) has long been a staple of management of the postmenopausal life phase. Over time, and after estrogen therapy was modified to include progestin, an increasing number of observational reports suggested that HRT conferred benefits well beyond those of managing or minimizing not flashes, mood swings, and vaginal dryness. In short, HRT was believed to improve women's health and even extend life. One of the most significant theorized benefits was protection against cardio- and cerebrovascular events. Other benefits--protection against osteoporosis, reduction in incontinence symptoms, and improved cognition--have also been linked with HRT. The validity of these theories depended largely on observational studies and anecdotal reports, and only lightly (or not at all) on randomized clinical trial data. Nevertheless, significant clinical data refuting HRT's proposed benefits has been available for several years. Findings from these investigations, including new results from two very large trials, show that beyond managing traditional menopause symptoms, HRT has little or no role in protection against certain diseases or conditions associated with aging. Indeed, long-term use of HRT may be contraindicated in most older women with intact uteruses.

J Hum Hypertens 2002 Jul;16(7):509-16 Related Articles, Books, LinkOut

The effect of hormone replacement therapy on arterial blood pressure and vascular compliance in postmenopausal women with arterial hypertension.

Kawecka-Jaszcz K, Czarnecka D, Olszanecka A, Rajzer M, Jankowski P.
I Cardiac Department, Jagiellonian University Medical College, Krakow, Poland.

Arterial pathology is a major contributor to cardiovascular disease, morbidity and mortality. Women are at higher risk of cardiovascular disease after menopause. Arterial stiffness determined by pulse wave velocity, increases with age both in men and women, whereas arterial compliance in premenopausal women is greater than in men of similar age. This difference is lost in the postmenopausal years, with evidence of rapid decline in arterial compliance in the perimenopausal period. Loss of hormonal modulation is a likely explanation for reduced arterial compliance in postmenopausal women. Long-term treatment with hormone replacement therapy (HRT) may be expected to partially reverse the increase in arterial stiffness. The aim of the study was to analyse the effect of HRT on blood pressure and arterial compliance in postmenopausal women with arterial hypertension receiving hypotensive drugs. The results in the present study of postmenopausal women with mild to moderate arterial hypertension receiving HRT showed only a transient tendency towards lower blood pressure. In our study HRT was found to improve arterial compliance at 3 months after HRT, and the effect was maintained throughout 12 months. The increased arterial compliance in women receiving HRT was independent of blood pressure. In parallel with decreasing pulse wave velocity women receiving HRT had lower total and low-density lipoprotein cholesterol. The conclusions were that after 1 year HRT in postmenopausal women with arterial hypertension improves circadian blood pressure pattern, but it does not affect significantly blood pressure values and variability. The present study also shows that HRT significantly inhibits age-related rigidity of large arteries.

Hormonal Replacement Therapy. Benefits and Risks
[Article in Spanish]

Lapidus AM.
Unidad de Internacion de Obstetricia del Hospital Juan A. Fernandez, Buenos Aires, Argentina.

A woman lives an average of between 25 to 30 years since the beginning of menopause. This period of life is characterized for the appearance of chronic diseases. Estrogens are effective in controlling vasomotor symptoms and also over the loss of bone mineral density, therefore lowering the risk of fractures in about 25-30%. The use of unopposed estrogens (without progesterone) raises 8 to 10 times the risk of endometrial and 2 to 3 times the risk of deep venous thrombosis as well. Until now, no raise was seen in breast cancer in short treatments (less than 5 years) especially if they are not opposed with progesterone. The recent publication of the surprising data of the trial Women's Health Initiative demonstrates a significative but small increase in the risk of breast cancer associated with the use of combined estrogen/progestin therapy proportional to the duration of the treatment. The reduction of the plasmatic levels of low density lipoproteins associated with the use of Hormonal Replacement Therapy (HRT), has not been linked to evident cardiovascular protection. There is a higher cardiovascular risk with the use of HRT in the first year of the treatment. No clear benefit of HRT has been associated to treatment of Alzheimer disease, and is still under investigation its role in the prevention of the disease. Conclusions: 1) A careful analysis of advantages and risks of HRT must be done before its use. 2) The treatment must be instituted on an individual basis and should be discussed with each patient.

Hormone replacement therapy with estradiol valerate and cyproterone acetate: effects on endothelium-dependent vasodilatation and arterial wall compliance.

Mares P, Dauzat M, Abramovici Y.
Department of Gynecology and Obstetrics, University Hospital Center, Nimes, France

OBJECTIVE: to evaluate changes in vasomotor endothelium function and elastic properties of the brachial artery in postmenopausal women beginning hormone replacement therapy (HRT) with Climen(R), a 28-day sequential therapy combining estradiol valerate (E2V) 2 mg/day D1-D21 with cyproterone acetate (CPA) 1 mg/day D12-D22, followed by a 7-day treatment-free interval. METHODS: Thirty-one women with natural or surgical menopause were included in an open multicenter study. Before treatment, at the end of the estrogen-only phase of cycle 1, and after the combined phase in cycles 1 and 3, endothelium-dependent vasodilatation (EDVD%) in the brachial artery was measured by the post-ischemia increase of the inner diameter, and pulse wave velocity (PWV) was measured in the same artery by simultaneous continuous wave Doppler and photo-plethysmography. RESULTS: compared to pre-treatment values, the median increase in EDVD was 14.3% after cycle 1 (P=0.0001) and 27.9% after cycle 3 (P=0.0001). CPA did not alter the effect of E2V on EDVD in cycle 1. Median arterial systolic pressure was unchanged, but median diastolic pressure fell from 70 to 67.5 mmHg (P=0.04) after cycle 3. Median PWV was reduced by 0.76 m/s after cycle 3 (relative reduction -9.3%) (P=0.035). There was a significant correlation between PWV and EDVD changes from pre-treatment values at the end of the 3rd cycle. CONCLUSION: treatment of postmenopausal women with E2V/CPA led to an immediate and significant improvement in endothelium-dependent vasodilatation. The estrogen-related vasomotor effect was not suppressed by the progestogen CPA. The WV changes are consistent with slower improvement of arterial compliance in some women. The non-invasive measurement of EDVD and PWV is a convenient method for the evaluation of both mechanical and functional effects of combination HRT on the arterial wall.

Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women.

Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH.

Internal Medicine, Helen Hayes Hospital, Rte 9W, West Haverstraw, NY 10993. lindsayr@helenhayeshosp.org

CONTEXT: Lower-than-commonly-prescribed doses of conjugated equine estrogens (CEEs) with medroxyprogesterone acetate (MPA) improve vasomotor symptoms and vaginal atrophy, provide acceptable bleeding and lipid profiles, and afford endometrial protection. This lower-dose therapy's protection against loss of bone mineral density (BMD) associated with menopause has not been thoroughly investigated. OBJECTIVE: To determine the effects of lower doses of CEEs only or CEEs-MPA on spine and hip BMD, total body bone mineral content (BMC), and biochemical markers of bone turnover in postmenopausal women. DESIGN AND SETTING: Two-year randomized, double-blind, placebo-controlled substudy of the Women's Health, Osteoporosis, Progestin, Estrogen trial, conducted at 19 US centers between August 1995 and October 2000. PARTICIPANTS: Eight hundred twenty-two healthy postmenopausal women aged 40 to 65 years who were within 4 years of their last menstrual period. INTERVENTIONS: Patients were randomly assigned to receive CEEs, 0.625; CEEs, 0.625 and MPA, 2.5; CEEs, 0.45; CEEs, 0.45 and MPA, 2.5; CEEs, 0.45 and MPA, 1.5; CEEs, 0.3; CEEs 0.3 and MPA, 1.5 (all doses in mg/d); or placebo for 2 years. All participants also received elemental calcium at 600 mg/d. MAIN OUTCOME MEASURES: Changes from baseline in spine and total hip BMD, total body BMC, and biochemical markers of bone turnover (serum osteocalcin and urinary cross-linked N-telopeptides of type I collagen), assessed at 6-month intervals and compared among treatment groups with a modified intention-to-treat approach. RESULTS: At 24 months, women assigned to all of the active treatment groups had significant gains from baseline (P<.001) in spine and hip BMD and total body BMC (except total body BMC in the group receiving CEEs, 0.3 mg/d). These changes were significantly different from those in the placebo group, in which losses of bone mass in spine and total body were evident over the course of the study (P<.001). The loss in hip BMD from baseline in the placebo group was significant at 18 (P =.02) but not at 24 months (P =.06). Osteocalcin and N-telopeptides of type I collagen were significantly reduced from baseline (P<.001) for all active treatment groups at all time points; no changes were found for the placebo group. For women treated with CEEs alone, the gains in spine BMD for the group taking CEEs, 0.625 mg/d, were significantly higher than those of the group taking CEEs, 0.3 mg/d (P =.02), but not the group treated with CEEs, 0.45 mg/d (P =.48). CONCLUSIONS: Doses of CEEs or CEEs-MPA lower than 0.625 mg/d effectively increase BMD and BMC in early postmenopausal women.

Am J Obstet Gynecol 2002 Apr;186(4):832-5 Books, LinkOut

Effects of the selective estrogen receptor modulator, raloxifene, on carotid artery pulsatility index in postmenopausal women.

Setacci C, la Marca A, Agricola E, Morgante G, Setacci F, Cappelli A, Petraglia F, De Leo V.
Institute of Vascular Surgery and the Institute of Gynecology and Obstetrics, Siena University, Siena, Italy; and Cardiologia Diagnostica, hospital San Raffaele, Milan, Italy.

OBJECTIVE: Estrogen replacement therapy after menopause reduces the incidence of arterial disease and cerebrovascular events. The reduced incidence also seems to be due to a positive effect of estrogens on brain blood flow as shown by a decrease in the carotid artery pulsatility index. Raloxifene, a second-generation selective estrogen receptor modulator, has aroused considerable interest because of its tissue-specific agonist-antagonist effect on estrogen receptors. However, there have been no studies on the effect of raloxifene on carotid blood flow after menopause. METHODS: A total of 66 healthy women in postmenopause for more than a year were divided randomly into 2 groups: the first group (n = 33; mean age +/- SD, 53.3 +/- 5.2 years) was treated with raloxifene (one 60-mg capsule per day) for 6 months, and the other group (n = 33; mean age +/- SD, 51.9 +/- 4 years) was untreated. Doppler ultrasonography was used to measure carotid artery pulsatility index (PI) at the beginning of the study and at 2-month intervals. RESULTS: A reduction in carotid artery PI was observed in all patients receiving raloxifene. No significant changes were observed in the control group. The reduction with respect to baseline values was 6.1%(P <.05) after 2 months, 11.2% (P <.05) after 4 months, and 13.2% (P <.05) after 6 months of therapy.The higher the baseline PI, the greater was its reduction after therapy. CONCLUSIONS: After 6 months of therapy, raloxifene induced a reduction in PI similar to that reported after estrogen therapy. The present results further our understanding of the mechanisms by which raloxifene might reduce the incidence of cardiovascular disease in postmenopausal women

Complementary/alternative therapies for reducing hot flashes in prostate cancer patients: reevaluating the existing indirect data from studies of breast cancer and postmenopausal women.

Moyad MA.
Department of Urology, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0330, USA. moyad@umich.edu

Vasomotor hot flashes are a common problem in women who are postmenopausal or receiving antiestrogen treatment for breast cancer. Hot flashes are also a common problem after orchiectomy/luteinizing hormone-releasing hormone therapy, occurring generally in 50% to 66% of these men. Prescribed treatments for hot flashes for men on hormonal ablation treatment for prostate cancer are well documented. These conventional agents have shown good results, but their long-term efficacy, safety, and cost are still questioned. Therefore, the search for other viable agents, including nontraditional treatments, continues. Complementary/alternative treatments to alleviate hot flashes in women have generated an enormous amount of interest. However, these options have received little attention in men with hot flashes. Research with vitamin E, soy, black cohosh, red clover, and numerous other alternative treatments in women may provide some indirect but valuable insight on their potential effectiveness in men. Many of these alternatives have been a disappointment in recent randomized trials of women, and it is likely that there will be similar results with men. However, numerous supplements have yet to be tested in a clinical trial against a placebo, and clinicians should become aware of this ever-increasing list. Patients should be made aware of the primary importance of lifestyle interventions that could partially affect hot flashes and immediately affect overall health, especially during the period of androgen suppression, when it is not uncommon to observe accelerated weight changes and insulin insensitivity. Otherwise, recent research with older and newer conventional agents, such as antidepressants or estrogen/progesterone, should be emphasized at this time for moderate-to-severe hot flashes that profoundly affect daily activities and/or sleep. Antidepressant supplements (St. John's wort) or acupuncture could also be an attractive option in future investigations. Low-dose estrogen seems particularly attractive, because it is inexpensive and may simultaneously reduce hot flashes and the risk of osteoporosis in men receiving long-term androgen suppression therapy; however, the potential for cardiovascular complications must be further investigated. Ultimately, adequate research (vs placebo) should determine the fate of the alternative supplements proposed for hot flash reduction.

Differential Effects of Oral Estrogen versus Oral Estrogen-Androgen Replacement Therapy on Body Composition in Postmenopausal Women.

Dobs AS, Nguyen T, Pace C, Roberts CP.
Johns Hopkins University School of Medicine (A.S.D., T.N.), Baltimore, Maryland 21287.

Menopause is associated with decreased lean body mass and increased fat due to aging and declining hormone secretion. Estrogens or estrogen-progestins have been used to alleviate vasomotor symptoms. However, estrogen-androgen (E/A) therapy is also used for vasomotor symptom relief and has been shown to increase lean body mass while decreasing fat mass. The objective of this 16-wk, double-blind, randomized, parallel group clinical trial was to compare esterified estrogen plus methyltestosterone (1.25 mg estrogen + 2.5 mg methyltestosterone/d; E/A group) vs. esterified estrogen alone (1.25 mg/d; E group) on body composition. Forty postmenopausal women (mean age, 57 yr) participated. Compared with estrogen treatment alone, women in the E/A group increased their total lean body mass and reduced their percentage fat for all body parts (P < 0.05). After E/A treatment, there were statistically significant increases in lean body mass by 1.232 kg [0.181 +/- 0.004, 0.81 +/- 0.057, and 0.24 +/- 0.009 kg in the upper body (P = 0.021), trunk (P = 0.001), and lower body (P = 0.047), respectively]. In the E group, the increase was 0.31 +/- 0.004, 0.021 +/- 0.03, and 0.056 +/- 0.05 kg in the upper body, trunk, and lower body, respectively. In the E/A group, body fat was reduced by 0.90 kg (P = 0.18 for the trunk only), and percentage body fat declined by 7.4% (P </= 0.05 for all body parts). Lower body strength increased by 23.1 kg (51 lb) in the E/A group vs. only 11 kg (24.25 lb) in the E group (P = 0.002 between groups). A statistically significant increase in weight (2.7 +/- 5.1 vs. 0.1 +/- 4.6 lb; P < 0.05) was observed in the E/A group compared with the E group. When subjects were given self-reporting questionnaires, more improvement was noted in sexual functioning and quality of life in the E/A group when compared with patients receiving E alone. There were no noteworthy side effects. In conclusion, E/A replacement therapy can improve body composition, lower-body muscle strength, quality of life, and sexual functioning in postmenopausal women

J Clin Oncol 2002 Mar 15;20(6):1449-1455

Effect of Soy Phytoestrogens on Hot Flashes in Postmenopausal Women With Breast Cancer: A Randomized, Controlled Clinical Trial.

Van Patten CL, Olivotto IA, Chambers GK, Gelmon KA, Hislop TG, Templeton E, Wattie A, Prior JC.
British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver Hospital and Health Sciences Centre, and University of British Columbia, Vancouver, British Columbia, Canada.

PURPOSE: Vasomotor symptoms, such as hot flashes and night sweats, in breast cancer survivors are often worsened by chemotherapy and tamoxifen, and/or the discontinuation of hormone replacement therapy at diagnosis. This study evaluated the acceptability and effectiveness of a soy beverage containing phytoestrogens as a treatment for hot flashes in postmenopausal women with breast cancer. METHODS: A randomized, placebo-controlled, double-blind clinical trial was conducted in postmenopausal women with moderate hot flashes who were previously treated for early-stage breast cancer. Women were stratified for tamoxifen use and randomized to a soy beverage (n = 59) containing 90 mg of isoflavones or to a placebo rice beverage (n = 64). Women recorded the number and severity of hot flashes daily with a daily menopause diary for 4 weeks at baseline and for 12 weeks while consuming 500 mL of a soy or placebo beverage. RESULTS: There were no significant differences between the soy and placebo groups in the number of hot flashes or hot flash scores. However, presumably because of a strong placebo effect, both groups had significant reductions in hot flashes. Mild gastrointestinal side effects were experienced by both groups but occurred with greater frequency and severity with soy. The mean serum genistein concentration at 6 weeks was significantly higher in women who consumed soy (0.61 +/- 0.43 &mgr;mol/L) compared with placebo (0.43 +/- 0.37 &mgr;mol/L) (P =.02). Overall acceptability and compliance were high and similar in both groups. CONCLUSION: The soy beverage did not alleviate hot flashes in women with breast cancer any more than did a placebo. Future research into other compounds is recommended to identify safe and effective therapies for hot flashes in breast cancer survivors.

J Bone Miner Res 2002 Mar;17(3):

Does hormone-replacement therapy prevent fractures in early postmenopausal women?

Randell KM, Honkanen RJ, Kroger H, Saarikoski S.

Department of Obstetrics and Gynecology, Kuopio University Hospital, Finland.

The purpose of this population-based prospective cohort study was to examine the effect of hormone-replacement therapy (HRT) on the risk of fractures. The study population consisted of 7217 postmenopausal women aged 47-56 years (mean, 53.3 years) at baseline from data taken from the Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) in Finland. We compared fracture incidences between HRT users and nonusers. A total of 679 (9.4%) women recorded validated fractures during the 5-year follow-up. Of these, 268 (39%) women had a distal forearm fracture. Two thousand six hundred seventy women (37%) had used HRT >6 months during the follow-up--one-half of them continuously. The relative risk, estimated as hazard ratio with Cox regression, was 0.69 (95% CI, 0.58-0.82) for any fracture and 0.49 (0.36-0.66) for distal forearm fracture among HRT users as compared with never-users. After adjusting for age, body mass index (BMI), number of chronic health disorders, fracture history, and time since menopause (independent risk factors) the corresponding risks were 0.67 (0.55-0.81) and 0.53 (0.37-0.74), respectively. The respective adjusted risks for continuous HRT users were 0.62 (0.48-0.79) and 0.41 (0.26-0.67). The adjusted risk of other than distal forearm fracture was 0.74 (0.55-0.98). The results suggest that HRT has a beneficial effect on prevention of fractures in general and on that of distal forearm fracture in particular in early postmenopausal women

Nutrition 2002 Feb;18(2):178-188 

Estrogen, statins, and polyunsaturated fatty acids: similarities in their actions and benefits---is there a common link?

Das UN.
EFA Sciences LLC, Norwood, Massachusetts, USA

OBJECTIVES: To investigate whether there is any common link between estrogen, statins, and polyunsaturated fatty acids (PUFAs), which have similar actions and benefits.METHODS: To critically review the literature pertaining to the actions of estrogen, statins, and various PUFAs.RESULTS: Estrogen, statins, and PUFAs enhance nitric oxide synthesis, suppress the production of proinflammatory cytokines such as tumor necrosis factor[alpha], interleukin-1, interleukin-2, and interleukin-6, show antioxidant-like and antiatherosclerotic properties, have neuroprotective actions, and by themselves or their products inhibit tumor cell proliferation and improve osteoporosis. Estrogen, statins, and PUFAs not only have similar actions but also appear to interact with each other. For instance, the binding of estrogen to its receptor on the cell membrane may be determined by its lipid content, statins and PUFAs inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, statins influence the metabolism of PUFAs, and PUFA deficiency enhances 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Statins and PUFAs inhibit tumor cell proliferation, suppress ras activity, and may prevent neurodegeneration and improve cognitive functions such as learning and memory. This suggests that PUFAs might be mediators of the actions of statins. Estrogen boosts cognitive performance in women after menopause and may protect against Alzheimer's disease.CONCLUSIONS: The common link between estrogen, statins, and PUFAs may be nitric oxide. Hence, a combination(s) of estrogen or its derivatives, statins, and various PUFAs may form a novel approach in the management of various conditions such as hyperlipidemias, coronary heart disease, atherosclerosis, osteoporosis, cancer, neurodegenerative conditions, and to improve memory.

Maturitas 2002 Feb 26;41(2):97-104 

The effects of a soy rich diet on serum lipids: the Menfis randomized trial.

Chiechi LM, Secreto G, Vimercati A, Greco P, Venturelli E, Pansini F, Fanelli M, Loizzi P, Selvaggi L.
Department of Obstetrics and Gynaecology, University of Bari, Corso Alcide de Gasperi 495, 70125, Bari, Italy

Objective: To assess beneficial effects of a soy rich diet on the main biomarkers of cardiovascular health in menopause, compared with the effects of the hormone replacement therapy (HRT). Methods: 187 healthy asymptomatic postmenopausal women, aged 39-60, were recruited and randomized into three groups: a soy rich diet group, a HRT group, and a control group. Lipid profile, body mass index, blood pressure, endometrial thickness, uterine artery resistance index (RI), were evaluated in all the participants at the baseline, after 6 months, and at the end of the study. Results: After a 6-month intervention period, the lipid profile in the soy rich diet group showed a favourable outcome, similar to that observed in the HRT group, but compliance to the diet was low. Conclusion: Soy products may be used in the prevention of cardiovascular risk in postmenopausal women because of their efficacy in contrasting the negative effects of menopause on the cardiovascular system, but our findings should be confirmed; moreover, suitable strategies to improve the compliance have to be considered.

Dermatology 2002;204(1):17-22

Postmenopausal Aging of the Sebaceous Follicle: A Comparison between Women Receiving Hormone Replacement Therapy or Not.

Pierard-Franchimont C, Pierard GE.
Department of Dermatopathology, University Medical Center Sart Tilman, Liege, Belgium.

Background: The endocrine control of sebaceous follicles is complex in women. During aging, a decline in sebum output is often experienced. However, some women report increased seborrhea after the menopause. Objective: In this study, the follicular reservoir function was studied during the first decade following the menopause. Methods: Four evaluations were made at 3-week intervals in two parallel age-matched groups of 50 postmenopausal women receiving hormone replacement therapy (HRT) or not. The Sebumeter served to measure the casual sebum level and the sebum excretion rate on the forehead. In addition, a Visioscan([reg]) equipped with an ultraviolet-recording camera was used with and without lipid-sensitive tapes interposed between the camera and the skin surface. Follicular openings and sebum pore patterns were studied by image analysis. Results: There was enormous diversity among individual values of sebum output at the skin surface. In untreated women, a significant decline in sebum excretion rate accompanied by an increase in both the sebum replacement time and the mean pore size were evidenced during the first decade after the menopause. The sebum excretion rate and casual level showed a wide range of interindividual differences early after the menopause. These physiological changes were less prominent in women receiving HRT. Conclusion: Postmenopausal aging affects the sebum production, but HRT does not significantly control the complex process of seborrhea. However, HRT mitigates the progressive enlargement of the openings of the sebum follicular reservoir. Copyright 2002 S. Karger AG, Basel

Hum Reprod 2002 Feb;17(2):497-502 

Hormone replacement therapy can augment vascular relaxation in post-menopausal women with type 2 diabetes.

Perera M, Petrie JR, Hillier C, Small M, Sattar N, Connell JM, Lumsden MA.
Department of Obstetrics and Gynaecology, University of Glasgow, G3 8SJ, Department of Medicine and Therapeutics, Western Infirmary, University of Glasgow, G11 6NT, Vascular assessment unit, Glasgow Caledonian University, G12 8QQ, Diabetes Centre, Gartnavel General Hospital, North Glasgow Hospitals University NHS Trust, Department of Pathological Biochemistry, University of Glasgow, G31 2ER, Department of Medicine and Therapeutics, Western Infirmary, University of Glasgow, G11 6NT and Department of Obstetrics and Gynaecology, University of Glasgow, Glasgow, UK.

BACKGROUND: Diabetes is a major risk factor for coronary heart disease in women and event rates increase substantially after the menopause. Observational studies have suggested that estrogens may provide cardioprotection by regulating endothelial nitric oxide synthase. METHODS: In order to examine the effect of hormone replacement therapy (HRT) on endothelium-dependent and -independent vascular relaxation in post-menopausal women with type 2 diabetes, an open study was conducted in which gluteal biopsies were collected from 17 women before and after 6 months of transdermal 17[beta]-estradiol (80 [micro]g twice weekly) in combination with oral norethisterone (1 mg daily). Small arteries (<550 [micro]m) were dissected from fat and mounted on a wire myograph for assessment of relaxation in response to acetylcholine (ACh), bradykinin (BK) and sodium nitroprusside (SNP). RESULTS: Maximal relaxation responses to ACh, BK and SNP in women with diabetes and non-diabetic control subjects were 52 [plus minus] 8 versus 96 [plus minus] 2% (P < 0.05), 76 [plus minus] 7 versus 97 [plus minus] 1%, (P < 0.05) and 91 [plus minus] 2 versus 98 [plus minus] 1% (P < 0.05) respectively. After 6 months of HRT, maximal relaxation responses to ACh, BK and SNP in women with diabetes (compared with pre-HRT) were: 88 [plus minus] 4 (P < 0.05), 93 [plus minus] 3 (P < 0.05) and 98 [plus minus] 1% (P < 0.05) respectively. At baseline and after HRT, EC(50) (concentration required to obtain 50% of maximum response) data exhibited similar changes. CONCLUSIONS: HRT had potentially beneficial effects on vascular relaxation. Data were consistent with improvements in endothelial function, vascular smooth muscle function, or both. Controlled studies are required to confirm and extend these findings.

Postgrad Med 2002 Jan;111(1):23-30; quiz 3 Related Articles, Books, LinkOut 

Estrogens and lipids. Can HRT designer estrogens, and phytoestrogens reduce cardiovascular risk markers after menopause?

Ariyo AA, Villablanca AC.
Division of Cardiovascular Medicine, University of California, Davis, Medical Center, Sacramento, USA.

HRT may act preventively to reduce morbidity and mortality from cardiovascular disease in primary prevention. The development of SERMs adds a new, exciting, and promising therapeutic option to this field, as does the enhanced availability of soy phytoestrogen products. Although clinical trial data are incomplete, epidemiologic studies suggest that HRT raises HDL-C and triglyceride levels and lowers LDL-C levels. In addition, HRT lowers levels of Lp(a). These changes account for up to 50% of the cardiovascular risk reduction observed with HRT. In contrast, SERMs have less uniform effects. Both SERMs and phytoestrogens are less potent than HRT but have greater tissue selectivity. Although further study is needed, current information suggests that SERMs and phytoestrogens have significant potential to reduce CAD risk and may be a viable alternative to HRT for modest lowering of lipid levels. Phytoestrogens may be particularly useful for reducing CAD risk in men because they do not cause the side effects associated with estrogen. Additional clinical trials are necessary to determine whether the favorable lipid effects associated with HRT, SERMs, and phytoestrogens are linked to protection against cardiovascular disease. Nonetheless, physicians should consider the use of HRT, SERMs, and phytoestrogens for lowering lipid levels and reducing cardiovascular risk in women.

Maturitas. 2002 Jan 30;41(1):69-77.

Androgens and estrogens in relation to hot flushes during the menopausal transition.

Overlie I, Moen MH, Holte A, Finset A.
Department of Behavioural Sciences in Medicine, University of Oslo, P.O. Box 1111, Blindern, N-0317, Oslo, Norway

In this paper, the association of hormones to vasomotor complaints during the menopausal transition is discussed. Fifty-seven regularly menstruating women without history of hormone replacement therapy (HRT) were selected for a longitudinal, prospective study around the menopausal transition. The mean age at the start of the study was 51.3 (+/-2.0) years. At intervals of 12 months all women went through a semi-structured interview and filled in questionnaires. Venous blood samples were collected every 12-month for analyses of estradiol (E2), testosterone, androstendione, dehydroepiandrosterone-sulphate (DHEA-S), follicle stimulating hormone (FSH), thyrotropin (TSH), and luteinizing hormone (LH). Vasomotor complaints were tested using questions about hot flushes and bouts of sweating in terms of occurrence, frequency and degree of distress. Forty-six percent of the subjects reported hot flushes and bouts of sweating before menopause, increasing to 67% during the first year after menopause and 49% in the second year postmenopause. Low levels of estradiol and high levels of FSH were associated with vasomotor complaints before menopause. During menopause high levels of TSH were related to vasomotor complaints. The first year after menopause, women, who at this point achieved hot flushes, were characterised by high levels of E2, but declining and low levels of FSH, but increasing. Postmenopausal, high levels of testosterone and DHEA-S seemed to protect against vasomotor symptoms. Our most important finding was, that among women who achieved hot flushes at the first assessment postmenopause, the high androgen levels was a significant predictor of recovery from hot flushes at the last assessment, 1 year later.

Maturitas. 2002 Jan 30;41(1):61-8.

Self-awareness during the menopause.

Bloch A.
Universitatsklinik fur Psychiatrie, Bereich Klinische Psychodiagnostik, Wahringer Gurtel 18-20, A-1090, Vienna, Austria

Objective: The aim of the study was to test the hypothesis that body-image and self-esteem are major contributors to the severity of menopausal symptoms, and furthermore to measure the influence of hormonal therapy and postmenopausal oestrogen level on specific complaints such as vasomotor symptoms. Methods: For the random check 51 patients, aged 43-63 (x=53.8; s=4.4) of an independent medical institution for menopause referred to as 'Viennese ambulance' were questioned. Results: It turned out, that their attitude towards menopause was of major influence on the degree of specific symptoms (e.g. depression, misery, headache etc.)-women who had a negative attitude towards the menopause suffered much more from such symptoms than women who had a positive one. Moreover, women who were satisfied with their physical appearance experienced fewer troublesome symptoms. There was a significant association between high self-esteem and fewer menopausal symptoms. The higher the self-esteem, the lower the symptoms. Conclusion: Women with a postmenopausal oestrogen level did not experience more menopausal symptoms than women with an average oestrogen level. Moreover, the symptoms were neither fewer nor more whether the women had undergone a hysterectomy or not whether they got hormonal treatment or not. That refutes the hypothesis, that the decrease of the oestrogen level during menopause is the main reason for the accompanying complaints.

Judith F. Barnes a , Elizabeth Farish a * , Marion Rankin b and David M. Hart b 
Received: 12/12/2000. Revised: 5/16/2001. Accepted: 5/31/2001. 

Abstract

In a study comparing the effects of two continuous HRT regimens on cardiovascular risk markers, 43 postmenopausal women were randomly assigned to receive either tibolone 2.5 mg/day ( n =20) or 0.625 mg/day conjugated equine oestrogens plus continuous medroxyprogesterone acetate 5 mg/day ( n =23). Serum lipoprotein levels, including LDL and HDL subfractions, oxidisability of LDL and serum nitrate/nitrite levels were determined before and during 12 weeks of therapy. Tibolone significantly reduced triglycerides (17.1%, P <0.01), HDL cholesterol (22.2%, P <0.001), and the ratio HDL 2 /HDL 3 cholesterol (20.2%, P <0.01). Total LDL cholesterol levels did not change significantly, although there was a downward trend in the LDLIII subfraction (12.0% reduction; P =0.06), percentage changes being positively correlated with percentage changes in triglyceride levels ( r =0.60, P <0.01). Susceptibility of LDL to oxidation was significantly decreased ( P <0.001), changes in lag-time being highly negatively correlated with percentage changes in levels of both LDLIII ( r =-0.68, P <0.01) and triglycerides ( r =-0.63, P <0.01). Nitrate/nitrite levels did not change. In contrast, the combined therapy caused a significant reduction in LDL cholesterol levels (11.1%; P <0.01) as a result of a significant decrease in the LDLI+II subfraction (12.8%; P <0.05). Changes in LDLI+II and LDLIII were correlated with changes in triglyceride levels ( r =-0.52, P <0.05 and r =0.63, P <0.01, respectively). No other parameter was significantly modified. Between treatment effects were significantly different on triglycerides ( P <0.01), HDL cholesterol ( P <0.001), LDL oxidation ( P <0.01) and LDLI+II:LDLIII ratio ( P <0.05). The reduction in LDL induced by the continuous combined therapy is likely to be beneficial, despite the apparent shift towards the LDLIII subfraction. Changes in oxidisability and subfraction profile of LDL indicate that tibolone may have a more favourable effect on cardiovascular risk than previously suggested.

Affiliations:

a Department of Biochemistry, Stobhill Hospital, Glasgow G21 3UW, UK. b Department of Gynaecology, Stobhill Hospital, Glasgow G213UW, UK. 

Med Sci Sports Exerc 2002 Jan;34(1):74-82 Related Articles, Books, LinkOut 

Menopause, estrogen, and training effects on exercise
hemodynamics: the HERITAGE study.

Green JS, Stanforth PR, Gagnon J, Leon AS, Rao DC, Skinner JS, Bouchard C, Rankinen T, Wilmore JH.

Department of Health and Kinesiology, Texas A&M University, College Station, TX; Laboratory of Molecular Endocrinology, CHUL Research Center, and Physical Activity Sciences Laboratory, Laval University, Quebec City, Canada; School of Kinesiology and Leisure Studies, University of Minnesota, Minneapolis, MN; Division of Biostatistics, Washington University School of Medicine, St. Louis, MO; Department of Kinesiology, Indiana University, Bloomington, IN; and Pennington Biomedical Research Center, Baton Rouge, LA.

GREEN, J. S., P. R. STANFORTH, J. GAGNON, A. S. LEON, D. C. RAO, J. S. SKINNER, C. BOUCHARD, T. RANKINEN, and J. H. WILMORE. Menopause, estrogen, and training effects on exercise hemodynamics: the HERITAGE study. Med. Sci. Sports Exerc., Vol. 34, No. 1, 2002, pp. 74-82. PURPOSE: To investigate the influences of menopause, hormone replacement, and endurance exercise training on cardiovascular hemodynamics and oxygen uptake parameters during exercise in women. METHODS: Subjects were 338 premenopausal women, 29 postmenopausal women taking hormone replacement, and 28 postmenopausal women not taking hormone replacement, all enrolled in the HERITAGE Family Study. Hemodynamic and oxygen uptake data were gathered on a cycle ergometer at 50 watts (W), 60% peak oxygen uptake, and at peak exercise, both before and after a 20-wk regimen of endurance exercise training on a cycle ergometer. RESULTS: Systolic blood pressure (SBP) during peak exercise was found to be an average of 14 mm Hg less in postmenopausal women receiving hormones than in those not receiving hormones. Furthermore, menopause was associated with a 26.2 mm Hg higher SBP at 50 W power output, which remained physiologically significant after adjustment for age. At 50 W, postmenopausal women not taking hormones showed a 13.8 mm Hg greater training-induced reduction in SBP than those taking hormones. CONCLUSION: It was concluded that hormone replacement may be associated with a vasodilatory reserve at high exercise intensities and that endurance exercise training elicits favorable hemodynamic and oxygen uptake adaptations during exercise that are, in most instances, independent of menstrual status or hormone replacement.

Drugs 2001;61(15):2243-2262 Books, LinkOut 

Estradiol-Intranasal: A Review of its Use in the Management of Menopause.

Dooley M, Spencer CM, Ormrod D.
Adis International Limited, Auckland, New Zealand.

Estradiol-intranasal is a nasal spray formulation containing an aqueous solution of 17beta-estradiol that has a unique pulse-like pharmacokinetic profile. In a well designed, placebo-controlled trial estradiol-intranasal 200 to 400 &mgr;g/day significantly reduced the incidence and severity of climacteric symptoms in women with moderate to severe menopausal symptoms after 4 and 12 weeks' treatment. The efficacy of estradiol-intranasal 300 &mgr;g/day was similar to that of oral estradiol 2 mg/day in this and another double-blind placebo-controlled trial. This equivalent efficacy was maintained in a subgroup of women with initially severe symptoms, and in smokers. Reductions in the incidence of atrophic vaginal mucosa and genitourinary symptoms and increases in the karyopyknotic index achieved with estradiol-intranasal 300 &mgr;g/day were also similar to those observed with oral estradiol 2 mg/day. Assessments of the effects of estradiol-intranasal on the complications of menopause (increased risk of cardiovascular disease and osteoporosis) are ongoing; however, estradiol-intranasal (sequentially combined with a progestogen) produced significant beneficial effects on some lipid parameters and on markers of bone resorption and formation, and bone mineral density in postmenopausal women. Estradiol-intranasal had no significant effects on serum levels of most of the assessed haemostatic factors, or on angiotensinogen or insulin levels. Estradiol-intranasal 100 to 600 &mgr;g/day was generally well tolerated in clinical trials and most adverse events were mild to moderate. The most commonly reported events were nasal symptoms and mastalgia. There was no evidence of endometrial hyperplasia with up to 1 year's treatment with estradiol-intranasal 300 &mgr;g/day combined with a progestogen. The incidence of mastalgia and withdrawal or breakthrough bleeding was lower with estradiol-intranasal 300 &mgr;g/day than with oral estradiol 2 mg/day (both administered with a progestogen) in one trial. In another trial, the incidence of mastalgia was lower with estradiol-intranasal 300 &mgr;g/day than with estradiol transdermal 50&mgr;g (both administered with a progestogen). However, the overall incidence of adverse events was similar between the two treatments in this trial. CONCLUSIONS: Estradiol-intranasal 200 to 400 &mgr;g/day (optimal initiating dose 300 &mgr;g/day) reduces the incidence and severity of menopausal climacteric symptoms and has a good tolerability profile. Thus, evidence to date suggests that estradiol-intranasal is a useful treatment option for menopausal symptoms.

Fertil Steril 2001 Dec;76(6):1101-7 Related Articles, Books, LinkOut 

Long-term estrogen replacement is associated with improved nonverbal memory and attentional measures in postmenopausal women.

Smith YR, Giordani B, Lajiness-O'Neill R, Zubieta JK.
Department of Obstetrics and Gynecology, Ann Arbor, Michigan, USA

Objective: To determine the cognitive domains improved or preserved by long-term hormone replacement therapy (HRT).Design: A comprehensive neuropsychological test battery was administered to healthy postmenopausal women who had been treated or not treated with long-term HRT without interruption since menopause.Setting: Women were recruited by advertisement from a university town and surrounding areas.Patient(s): Women 60 years or older were studied who were treated (n = 16) or not treated (n = 13) with HRT.Intervention(s): Neuropsychological testing included tests of memory, verbal fluency, executive functions, attention and concentration, and psychomotor function. Tests of intellectual function, depressive symptoms, and emotional functioning assessed general functions and comparability of the groups.Main Outcome Measure(s): Neuropsychological testing scores were compared between groups.Result(s): No statistically significant differences between the groups were found for general demographic, intellectual, and psychological measures. Scores from both the Weschler Memory Scale Visual Reproduction (delayed recall) and the Digit Vigilance Test (attention) showed statistically significant better performance and fewer errors in the group of women on HRT.Conclusion(s): Long-term postmenopausal HRT is associated with higher scores in tests of nonverbal memory and attention.

1: Menopause 2001 Nov-Dec;8(6):433-40 Related Articles, Books, LinkOut 

Women's beliefs about "natural" hormones and natural hormone
replacement therapy.

Adams C, Cannell S.

1Center for the Study of Women in Society, University of Oregon, and 2 Broadway Apothecary, Eugene, Oregon, USA.

ABSTRACT : OBJECTIVE: To assess women's beliefs about natural hormones, including what they believe the term "natural" means, and their beliefs about the risks, side effects, and efficacy of natural hormone replacement compared to standard hormone replacement. DESIGN: Eighty-two women completed a 20-item survey available at a local compounding pharmacy. Respondents were white (100%), middle-aged (mean age, 47.22 years), and college educated (95.1%); 32.9% were perimenopausal, and 50.0% were postmenopausal; 58.5% were currently using hormone replacement therapy and, of those, 77.1% were using human bio-identical hormones. RESULTS: Ninety percent of the respondents ( n = 74) reported that they had heard about natural hormones. Of those, most believed natural meant plant-derived (44.6%) and/or not synthesized or made without chemicals (50.0%). Most reported hearing about natural hormones from a healthcare provider (66.2%) and/or magazines and books (55.4%). When compared with standard hormone replacement, most respondents endorsed the beliefs that natural hormones have fewer or no risks (71.4%), have fewer or no side effects (69.0%), and are equally or more effective for managing menopause symptoms (61.8%). In addition, many endorsed the beliefs that natural hormone replacement is equally or more effective than standard hormone replacement for protection against osteoporosis (47.1%) and heart disease (40.0%), although many endorsed "don't know" for bone (45.7%) and heart (54.3%) protection. CONCLUSIONS: Among women responding to a survey in a compounding pharmacy, most believed that, compared with standard hormones, natural hormones are safer, cause fewer side effects, and are equally or more effective for symptom management. Many believed natural hormone replacement is equally or more effective for long-term bone and heart protection. Educating women on the nature, risks, and benefits of natural hormone therapy is recommended.

Effect of hormone replacement therapy on nitric oxide bioactivity and monocyte chemoattractant protein-1 levels.

Koh KK, Won Son J, Yeal Ahn J, Lee SK, Young Hwang H, Sung Kim D, Kyu Jin D, Hoon Ahn T, Kyun Shin E.
Cardiology, Gachon Medical School, 405-760, Inchon, South Korea

Background: Vascular inflammation plays an important role in the pathogenesis of atherosclerosis. We investigated the effect of hormone replacement therapy (HRT) on vasomotor function and monocyte chemoattractant protein (MCP)-1 levels, an important serological marker of inflammation. Methods: We administered micronized progesterone (MP) 200 mg for 10 days with conjugated equine estrogen (CEE) 0.625 mg for 25 days and remaining 5 days off cyclically during 2 months to 20 healthy postmenopausal women (PMW). We measured NO bioactivity and plasma levels of MCP-1 before and after HRT in 20 PMW. And we measured plasma levels of MCP-1 in each 20 subjects of premenopausal women, men<50, and men>50 years, respectively. Results: MP combined with CEE significantly improved the percent flow-mediated dilator response to hyperemia relative to baseline measurements (P<0.001). PMW receiving HRT had lower levels of MCP-1 than those not receiving HRT (121+/-38 versus 146+/-44 pg/ml, P<0.001). In all comparisons, subjects with high estrogen status had significantly lower MCP-1 levels than subjects with low estrogen status (P<0.001 by ANOVA). Premenopausal women had lower levels of MCP-1 than men of a similar age (106+/-14 versus 164+/-40 pg/ml, P<0.001). PMW not receiving HRT had similar levels of MCP-1 compared with men of a similar age (146+/-44 versus 143+/-29 pg/ml, P=0.816). Premenopausal women had markedly lower levels of MCP-1 than PMW not receiving HRT (106+/-14 versus 146+/-44 pg/ml, P=0.001). PMW receiving HRT had similar levels of MCP-1 compared with premenopausal women (121+/-38 versus 106+/-14 pg/ml, P=0.323). Conclusion: These findings might provide at least a partial explanation for the protection against cardiovascular disease experienced by premenopausal women, and the loss of that protection following menopause.

1: Int Urogynecol J Pelvic Floor Dysfunct 2001;12(4):258-61

The role of estrogen supplementation in lower urinary tract dysfunction.

Hextall A, Cardozo L.
King's College Hospital, London, UK.

The female lower urinary and genital tracts both arise from the primitive urogenital sinus and develop in close anatomical proximity. Sex hormones have a substantial influence on the female lower urinary tract throughout adult life, with fluctuations in their level leading to macroscopic, histological and functional changes. Urinary symptoms may therefore develop during the menstrual cycle, in pregnancy and following the menopause. Estrogen deficiency, particularly when prolonged, is associated with a wide range of urogenital complaints, including frequency, nocturia, incontinence, urinary tract infections and the 'urge syndrome'. Estrogen supplementation subjectively improves urinary stress incontinence but there is no objective benefit when given alone; however, estrogen given in combination with phenylpropanolamine may be clinically more useful. Hormone replacement therapy does appear to treat postmenopausal irritative urinary symptoms such as frequency and urgency, possibly by reversing urogenital atrophy, and there is also evidence to suggest that estrogens can provide prophylaxis against recurrent urinary tract infections. However, the 'best' type of estrogen, route of administration and duration of therapy are at present unknown.

1: Menopause 2001 Sep;8(5):328-332

Postmenopausal hormonal support: discontinuation of raloxifene versus estrogen.

Kayser J, Ettinger B, Pressman A.
Division of Research, Kaiser Permanente Medical Care Program, Oakland, California, USA.

OBJECTIVE: To determine possible differences in continuation among women initiating treatment with the selective estrogen receptor modulator raloxifene, versus those initiating treatment with estrogen-containing regimens.
DESIGN: A pharmacy prescription database search for refill patterns. The study subjectswere members of Kaiser Foundation Health Plan, a large health maintenanceorganization; 1,394 women age >/=60 years who filled index prescriptions foreither raloxifene (n = 331) or systemic estrogens (n = 1,063) between April 1998and March 1999. The main outcome measure was discontinuation based oprescription refill patterns through December 2000.
RESULTS: At 24 months, the probabilities of discontinuing were 56% for women starting raloxifene comparedto 72% for women starting estrogens. The likelihood of discontinuation wassignificantly less among women starting raloxifene than among those startingestrogen (hazard ratio = 0.75; 95% confidence interval = 0.64-0.88). Adjustmentsfor age and prescriber specialty did not affect the risk.
CONCLUSIONS: Weconclude that discontinuation of estrogen by women well beyond the age ofmenopause is high; more than two-thirds discontinue within 2 years of starting.Women starting therapy with raloxifene are 25% percent less likely todiscontinue their medication than those starting estrogen, providing somepromise that long-term benefits of raloxifene may be more easily achieved thanthose of estrogen.

1: Br J Cancer 2001 Sep;85(5):674-677

A population-based cohort study of HRT use and breast cancer
in southern Sweden.

Olsson H, Bladstrom A, Ingvar C, Moller TR.
Department of Oncology, University Hospital, Lund, S-22185, Sweden

The overall tumour incidence and breast cancer incidence related to hormone replacement therapy (HRT) were followed in a population-based cohort of 29 508 women, aged 25-65 when interviewed in 1990-92. By the end of the follow up in December 1999, there were 226 611 person-years of observation. A total of 1145 malignant tumours were recorded (expected 1166.6; SIR = 0.98, 95% CI 0.93-1.04). There was a small excess of breast cancer with 434 observed and 387.69 expected (SIR = 1.12, 95% CI 1.02-1.23). Among about 3 663 ever users of HRT, there was no increase in overall tumour incidence (SIR = 0.98, 95% CI 0.86-1.12) but a significant excess of breast cancer (SIR = 1.35, 95% CI 1.09-1.64) compared with never users (SIR = 1.07, 95% CI 0.96-1.19). Breast cancer increased with increasing duration of use and for 48-120 months use the SIR was 1.92 (95% CI 1.32-2.70). There was no significant interaction with family history of breast cancer although an independent additive effect was suggested between HRT use and family history. In a Cox regression model time to breast cancer in relation to duration of HRT use was analysed adjusting for age at menarche, age at menopause, age at first full term pregnancy, parity and age at diagnosis. A significantly higher risk was seen for longer duration of HRT use compared with never users. No increased risk is seen in women beyond 5 years after stopping HRT.
There was no interaction between previous use of oral contraceptives and later HRT use. Copyright 2001 Cancer Research Campaign.

1: Neuroimage 2001 Oct;14(4):789-801

Effects of estrogen on patterns of brain activity at rest and during cognitive
activity: a review of neuroimaging studies.

Maki PM, Resnick SM.
Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock
Drive, Baltimore, Maryland, 21231

Animal and human studies provide evidence of systematic effects of estrogen on cerebral activity and cognitive function. In this article, we review studies of the activational effects of estrogen on cerebral activity during rest and during the performance of cognitive tasks in pre- and postmenopausal women. The goal is twofold-to better understand evidence suggesting that estrogen influences brain functioning and argue for the importance of considering hormone effects when designing neuroimaging studies. Hormone-related increases in blood flow during the resting state have been documented in healthy elderly women, elderly women with cerebrovascular disease, and middle-aged postmenopausal women with early menopause. There is no reliable influence of estrogen on blood flow during the resting state in women with Alzheimer's disease. Hormone therapy has been associated with changes in brain activation patterns in middle-aged and elderly postmenopausal women during performance of verbal and figural memory tasks, providing critical biological support for the view that estrogen might protect against age-associated changes in cognition and lower the risk of Alzheimer's disease. There is a paucity of studies examining changes in brain activation patterns across the menstrual cycle and a need for randomized studies of hormone therapy in postmenopausal women to confirm findings from observational studies.
General procedural guidelines for controlling and investigating hormone effects in neuroimaging studies are discussed.

1: Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001 Sep;92(3):276-280

Oral symptoms at menopause-the role of hormone replacement therapy.

Tarkkila L, Linna M, Tiitinen A, Lindqvist C, Meurman JH.
University of Helsinki, National Research and Development Centre for Welfare and
Health, and Helsinki University Central Hospital.

OBJECTIVE: A questionnaire was used to investigate the prevalence of self-assessed sensations of painful mouth (PM) and dry mouth (DM) in menopause-aged women. Special attention was paid to the association of the use of hormone replacement therapy (HRT) with oral symptoms. Our hypothesis was that women using HRT have fewer oral symptoms than those who do not use HRT.
Study Design: Patients were selected from among 50- to 58-year-old women attending a communal mammography screening program in Helsinki, Finland. Every fifth woman was offered a structured questionnaire. RESULTS: Completed questionnaires were received from 3173 women (response rate, 65%). Of the total sample, 46.8% (n = 1486) used HRT. The occurrence of PM was 8.2% (n = 259) and DM, 19.9% (n = 631).
Climacteric symptoms were reported by 24% (n = 761) of the total sample and by 19.2% (n = 285) of the HRT users. According to logistic regression analyses, climacteric symptoms were found to be predictive of PM (P =.000) and DM (P =.000). The use of HRT also increased the occurrence of PM (P =.03). However, as a single covariate in our statistical model, the use of HRT was not a predictor of PM. The use of HRT also did not correlate with the occurrence of DM.
CONCLUSIONS: The occurrence of PM and of DM seemed to be associated with climacteric symptoms in general, and the use of HRT did not prevent the oral symptoms studied.

1: Clin Sci (Lond) 2001 Aug;101(2):147-57

Effects of hormone replacement therapy and high-impact physical exercise on skeletal muscle in post-menopausal women: a randomized placebo-controlled study.

Sipila S, Taaffe DR, Cheng S, Puolakka J, Toivanen J, Suominen H.

Department of Health Sciences, University of Jyvaskyla, Box 35 (LL), FIN-40351 Jyvaskyla, Finland.

An age-related decline in muscle performance is a known risk factor for falling, fracture and disability. In women, a clear deterioration is observed from early menopause. The effect of hormone replacement therapy (HRT) in preserving muscle performance is, however, unclear. This trial examined the effects of a 12-month HRT and high-impact physical exercise regimen on skeletal muscle in women in early menopause. A total of 80 women aged 50-57 years were assigned randomly to one of four groups: exercise (Ex), HRT, exercise+HRT (ExHRT) and control (Co). The exercise groups participated in a high-impact training programme. The administration of HRT (oestradiol/noretisterone acetate) or placebo was carried out double-blind. Knee extension torque and vertical jumping height were evaluated. Lean tissue cross-sectional area (LCSA) and the relative proportion of fat within the muscle compartment were measured for the quadriceps and lower leg muscles. The ExHRT group showed significant increases in knee extension torque (8.3%) and vertical jumping height (17.2%) when compared with the Co group (-7.2%). Vertical jumping height also increased after HRT alone (6.8%). The LCSA of the quadriceps was increased significantly in the HRT (6.3%) and ExHRT (7.1%) groups when compared with the Ex (2.2%) and Co (0.7%) groups. Lower leg LCSA was also increased in the ExHRT group (9.1%) when compared with the Ex (3.0%) and Co (4.1%) groups. In addition, the increase in the relative proportion of fat in the quadriceps in the Co group (16.6%) was significant compared with those in the HRT (4.9%) and ExHRT (-0.6%) groups. Thus, in post-menopausal women, muscle performance, muscle mass and muscle composition are improved by HRT. The beneficial effects of HRT combined with high-impact physical training may exceed those of HRT alone.

1: Metabolism 2001 Aug;50(8):976-82

Abdominal fat distribution in pre- and postmenopausal women: The impact of physical activity, age, and menopausal status.

Kanaley JA, Sames C, Swisher L, Swick AG, Ploutz-Snyder LL, Steppan CM, Sagendorf KS, Feiglin D, Jaynes EB, Meyer RA, Weinstock RS.

Department of Exercise Science, Syracuse University, Syracuse, NY, USA.

Age-related increases in total body fat have been reported, but the impact of menopause on abdominal fat distribution is still unclear. The purpose of this study was to determine the impact of menopausal status on abdominal fat distribution using magnetic resonance imaging (MRI). In addition, we investigated the influence of abdominal fat distribution on blood lipid profiles and leptin concentrations. Twenty-three premenopausal (PRE), 27 postmenopausal (POST), and 28 postmenopausal women on estrogen replacement therapy (ERT) had measurements of regional abdominal fat, blood lipids, and serum leptin concentrations. The women were matched for body mass index (BMI) and total body fat mass. Age and menopausal status were not found to be significant predictors of total abdominal fat, visceral fat, or subcutaneous fat, while physical activity was a significant predictor (P <.01) for total abdominal fat (R(2) =.16), visceral fat (R(2) =.32) and percent visceral fat (R(2) =.25). There was a trend for a greater visceral fat content in the POST women compared with the PRE women (2,495.0 +/- 228.4 v 1,770.4 +/- 240.8 cm(2), respectively, P =.06). The percent visceral abdominal fat was significantly lower (P <.05) in the premenopausal women than in either postmenopausal group (PRE, 23.2% +/- 1.7%; POST, 28.9% +/- 1.8%; ERT, 28.9% +/- 1.6%). Menopausal status and age did not influence any of the blood lipid values. Abdominal fat distribution was a significant predictor of cholesterol concentrations and the cholesterol/high-density lipoprotein-cholesterol (HDL-C) ratio, but only accounted for approximately 15% of the variability in these levels. Total body fat and physical activity accounted for 47% of the variability in leptin concentrations, while abdominal fat distribution, age, and menopausal status were not significant predictors. In conclusion, in early postmenopausal women, the level of physical activity accounts for the variability in abdominal fat distribution observed, while menopausal status and age do not play a significant role. ERT was not associated with additional benefits in abdominal fat distribution compared with postmenopausal women not on ERT or in the blood lipid profile in these women. Copyright 2001 by W.B. Saunders Company

1: Arch Intern Med 2001 Jun 11;161(11):1448-54

Postmenopausal estrogen use, type of menopause, and lens opacities: the Framingham studies.

Worzala K, Hiller R, Sperduto RD, Mutalik K, Murabito JM, Moskowitz M, D'Agostino RB, Wilson PW.

Division of Epidemiology and Clinical Research, National Eye Institute, Bldg 31, Room 6A52, 31 Center Dr MSC 2510, Bethesda, MD 20892-2510, USA.

BACKGROUND: Previous studies of estrogen replacement therapy and lens opacities have not reported consistent findings. OBJECTIVE: To investigate whether postmenopausal estrogen use is associated with the occurrence of age-related lens opacities (nuclear, cortical, and posterior subcapsular). METHODS: Surviving members of the original cohort of the Framingham Heart Study who also participated in the Framingham Eye Study (1986-1989) were examined for the absence or presence of lens opacities. Data from the Framingham Heart Study, including information on menopausal status (collected biennially from approximately 1948) and use of estrogen replacement therapy (collected biennially from approximately 1960) were used to examine associations between lens opacities and duration of postmenopausal estrogen use, type of menopause, and age at menopause. Five hundred twenty-nine women, aged 66 to 93 years, were included. Multivariable-adjusted odds ratios of specific types of lens opacities were calculated for (1) duration of estrogen use (never and 1-2, 3-9, and >/=10 years), (2) surgical vs natural menopause, and (3) age at menopause. RESULTS: Longer duration of postmenopausal estrogen therapy was inversely associated with the presence of nuclear lens opacities in an adjusted model. Women who had taken estrogen for 10 years or longer had a 60% reduction in risk compared with nonusers (odds ratio, 0.4; 95% confidence interval, 0.2-1.01). Longer duration of estrogen use was associated with fewer posterior subcapsular opacities at a borderline level of significance. No association was noted for cortical opacities. The risk of posterior subcapsular opacities was significantly increased for women who had undergone surgical menopause compared with women with natural menopause (odds ratio, 2.2; 95% confidence interval, 1.1-4.3). No association was noted for lens opacities and age at menopause. CONCLUSION: Data from our study and other studies suggest that a reduction in the risk of lens opacities may be an additional benefit of postmenopausal estrogen use.

1: Fertil Steril 2001 May;75(5):898-915

Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: analysis of studies published from 1974-2000.

Godsland IF.

Endocrinology and Metabolic Medicine, Division of Medicine, Imperial College School of Medicine, London, United Kingdom Objective:

To establish reference estimates of the effects of different hormone replacement therapy (HRT) regimens on lipid and lipoprotein levels.Design: Review and pooled analysis of prospective studies published up until the year 2000.Setting: Clinical trials centers, hospitals, menopause clinics.Patient(s): Healthy postmenopausal women.Intervention(s): Estrogen alone, estrogen plus progestogen, tibolone, or raloxifene in the treatment of menopausal symptoms.Main Outcome Measure(s): Serum high- and low-density lipoprotein (HDL and LDL) cholesterol, total cholesterol, triglycerides, and lipoprotein (a).Result(s): Two-hundred forty-eight studies provided information on the effects of 42 different HRT regimens. All estrogen alone regimens raised HDL cholesterol and lowered LDL and total cholesterol. Oral estrogens raised triglycerides. Transdermal estradiol 17-beta lowered triglycerides. Progestogens had little effect on estrogen-induced reductions in LDL and total cholesterol. Estrogen-induced increases in HDL and triglycerides were opposed according to type of progestogen, in the order from least to greatest effect: dydrogesterone and medrogestone, progesterone, cyproterone acetate, medroxyprogesterone acetate, transdermal norethindrone acetate, norgestrel, and oral norethindrone acetate. Tibolone decreased HDL cholesterol and triglyceride levels. Raloxifene reduced LDL cholesterol levels. In 41 studies of 20 different formulations, HRT generally lowered lipoprotein (a).Conclusion(s): Route of estrogen administration and type of progestogen determined differential effects of HRT on lipid and lipoprotein levels. Future work will focus on the interpretation of the clinical significance of these changes.

1: Recenti Prog Med 2001 Mar;92(3):209-12

[Article in Italian] La Vecchia C.

Laboratorio di Epidemiologia Generale, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Istituto di Statistica Medica e Biometria, Università, Milano.

Although the use of hormone replacement therapy for menopause based on estrogens alone increases endometrial cancer risk, several studies indicate that combined therapy with estrogens and progestins is not related to an appreciable excess of endometrial cancer risk, if progestins are given for more than 10 or 14 days in each cycle. Combined therapy, however, may be associated to greater excess in breast cancer incidence as compared to estrogens alone.

1: Ann Med 2001 Feb;33(1):4-6

Managing the menopause: phyto-oestrogens or hormone replacement therapy? Eden JA. Menopause is a natural event, and understandably many women would like to take a natural therapy rather than a drug for managing their menopause symptoms as well as preventing the long-term sequelae of oestrogen deficiency. In this respect phyto-oestrogens show a lot of promise. However, at this point in time clinical data are inconclusive. There are some data supporting the contention that isoflavones improve hot flushes; however, there are also negative studies. Soy protein has been shown to lower cholesterol, and isoflavones improve arterial compliance. Clinical studies suggest that isoflavones have little impact on menopause-induced bone loss.

1: J Gend Specif Med 2001;4(1):60-3

Prevalence of hormone replacement therapy and antidepressant use in peri- and postmenopausal women.

Gartrell NK, Koh AS, Becker C, LaVoy A, Rosen S, Thiemann S.
Department of Psychiatry, University of California, San Francisco, USA.

OBJECTIVE: To examine the prevalence of hormone replacement therapy (HRT) and antidepressant use in peri- and postmenopausal women. DESIGN: Prevalence survey. SUBJECTS: Peri- and postmenopausal outpatients (N = 253) at five medical clinics. METHODS: Participants completed a 47-item questionnaire requesting information on mood changes associated with menstruation, childbirth, oral contraceptive use, and menopause. Peri- and postmenopausal participants were asked to rate the severity of dysphoric symptoms experienced during the menopausal transition and to specify whether HRT, antianxiety medication, or antidepressant medication relieved the symptoms. RESULTS: Forty percent of respondents experienced more severe depression than anticipated during menopause, but only 8% were treated with antidepressants. Forty-six percent of respondents were treated with HRT. CONCLUSIONS: The data suggest that antidepressant and antianxiety medications are more helpful than HRT in relieving peri- and postmenopausal depression or anxiety. However, most women managed the mood changes associated with menopause without psychopharmacologic intervention. This is consistent with other reports on the transitory nature of peri- and postmenopausal depression for most women.

Auditory brainstem response in postmenopausal women treated with hormone replacement therapy: a pilot study.

Caruso S, Cianci A, Grasso D, Agnello C, Galvani F, Maiolino L, Serra A
Department of Microbiological Science and Gynecological Science, School of Medicine, University of Catania, Italy.

OBJECTIVE: To research the nongenital audiological target for gonadal steroids in postmenopausal women who are treated with hormone replacement therapy. DESIGN: Fifty postmenopausal volunteers were treated with hormone replacement therapy. Women with an intact uterus had sequential weekly transdermal estradiol plus nomegestrole acetate 5 mg orally for 12 days per month or a continuous daily oral dose of conjugated estrogen 0.625 mg and medroxyprogesterone acetate 5 mg tablet. Eighteen surgically postmenopausal women received a weekly transdermal estradiol system. Twenty-five postmenopausal volunteers-5 with a natural menopause and 10 with a surgical menopause-and 20 premenopausal normally cycling women were used as a control group. Each woman performed auditory brainstem response by auditory-evoked potentials for waves I, III, and V and for interpeak I-III, I-V, and III-V intervals. RESULTS: Women who were treated with hormone replacement therapy showed wave latencies and interpeak latencies shorter than those for postmenopausal women in the control group (p < or = 0.05), overlapping those of the premenopausal women (p > 0.05). Women who were treated with estrogen replacement therapy showed shorter time latencies than those treated with combined hormone replacement therapy (p < or = 0.05). CONCLUSIONS: Our data suggest that fluctuating hormone levels cause changes in auditory brain-stem response waves, even if the exact mechanism of activity of the gonadal steroids is not clear. However, we believe that estrogen may influence the neuronal plasticity, the metabolic levels of neurotransmitters, and thus the neuronal conduction time into the audiological system.

The North American Menopause Society 1998 menopause survey: Part II. Counseling about hormone replacement therapy: association with socioeconomic status and access to medical care.

Ettinger B, Woods NF, Barrett-Connor E, Pressman A
Division of Research, Kaiser Permanente Medical Care Program, Oakland, California, USA.

OBJECTIVE: The purpose of this study was to examine two predictors of women's obtaining hormone replacement therapy (HRT) counseling: socioeconomic status and access to health care. DESIGN: During May-July 1998, by means of random-digit telephone dialing, 749 postmenopausal women who were living in the United States and aged 50-65 years were interviewed. On average, they were 56.8 years and 11.8 years postmenopausal. Most (86.0%) were Caucasian, and their median annual income was approximately $40,000. Nearly all (90.8%) had medical insurance coverage; 47.6% of those insured received care from a managed care organization. Access to medical care was evidenced by 92.3% being under the care of a primary care physician, 92.3% ever having had a mammogram, 96.9% ever having had a pelvic examination, and 91.1% ever having had a serum cholesterol determination. RESULTS: Of these 749 women, 75.4% reported that they had received counseling about post-menopausal HRT from healthcare providers. Both level of education and level of income were associated with an increased likelihood that HRT counseling would be obtained. Having a personal physician, and particularly receiving care from a gynecologist, increased the likelihood that counseling would be available. There were no substantial differences in counseling frequency between women in managed care plans and those having other types of health insurance. In a multivariate model, adjusted odds ratios for receiving HRT counseling were 2.9 (95% confidence interval [CI] = 1.7-4.8) for having an annual income of $50,000 or more versus less than $30,000, 2.8 (95% CI = 1.7-4.5) for receiving care from a gynecologist versus other primary care physician, 1.9 (95% CI = 1.1-3.2) for being Caucasian versus not, and 1.5 (95% CI 1.0-2.2) for having a hysterectomy versus not. CONCLUSIONS: Three quarters of a sample of US postmenopausal women aged 50-65 years reported that they had been counseled about HRT. However, women of lowest socioeconomic status and those who did not have a primary care physician were least likely to have received counseling. No differences were observed in prevalence of counseling between women in managed care settings and those with other types of health insurance. The findings suggest that special efforts are necessary to provide menopause education and counseling to underserved women.

1: Hum Reprod 2000 May;15(5):1028-1036

Safety and efficacy of oestriol for symptoms of natural or surgically induced menopause.

Takahashi K, Okada M, Ozaki T, Kurioka H, Manabe A, Kanasaki H, Miyazaki K
Department of Obstetrics and Gynecology, Shimane Medical University, 89-1, Enya-cho, Izumo 693-8501, Japan.

To assess the safety and efficacy of oestriol in relieving post-menopausal symptoms 53 post-menopausal Japanese women with climacteric symptoms, 27 with natural menopause (group I) and 26 with surgically induced menopause (group II), received oral oestriol, 2 mg daily for 12 months. Clinical parameters including Kupperman index (KI) and the degree of satisfaction with symptomatic relief; serum concentrations of oestradiol, FSH and LH; serum lipids; blood pressure; bone mineral density, serum calcium (Ca), alkaline phosphatase (ALP), and urinary Ca were compared between the two groups. Oestriol improved KI in groups I and II by 49 and 80% respectively. Satisfaction with treatment was 85% in group I and 93% in group II. For both parameters, values were significantly different between groups I and II (P < 0.05 for both). Serum concentrations of oestradiol, FSH and LH changed in group I versus group II 6 months after initiation. A significant decrease in serum ALP and Ca/Cr was observed in group I at 6 months. Except for serum triglycerides, oestriol had no significant effect on lipids. Systolic and diastolic blood pressures were significantly decreased in group I at 3 months versus baseline. Slight vaginal bleeding occurred in 14.3% of group I. Histological evaluation of the endometrium in all women of group I and ultrasound assessment of the breasts following 12 months of oestriol treatment found normal results in all women. Therefore, oestriol appeared to be safe and effective in relieving symptoms of menopausal women. The beneficial biochemical effects of oestriol were marked in the natural menopause. Overall, oestriol may serve as a good choice for hormone replacement therapy to protect against other climacteric symptoms in post-menopausal women who do not need medication for osteoporosis or coronary artery disease.

1: J Am Coll Cardiol 2000 May;35(6):1403-10

Phytoestrogens and cardiovascular health.

Lissin LW, Cooke JP
Stanford University Medical Center, California, USA.

Coronary artery disease is the leading overall cause of mortality for women and increases dramatically after menopause. Estrogen has many beneficial cardiovascular actions although concerns have been raised about its effects on the progression of breast and uterine neoplasms and its tendency to increase coagulability. Selective estrogen agonists may be superior to conventional estrogens. A dietary source of a partial estrogen agonist is the plant-based group of phytoestrogens, which include isoflavones, lignans and coumestans. Phytoestrogens have a similar structure to estradiol and have weak affinity for the estrogen receptor. Epidemiologic data indicate that women ingesting high amounts of phytoestrogens, particularly as isoflavones in soy products, have less cardiovascular disease, breast and uterine cancer and menopausal symptoms than those eating Western diets. Preclinical and clinical studies have found that isoflavones have lipid-lowering effects as well as the ability to inhibit low-density lipoprotein oxidation. They have been shown to normalize vascular reactivity in estrogen-deprived primates. Furthermore, phytoestrogens have antineoplastic effects with inhibition of cellular proliferation as well as angiogenesis, properties that could be protective against cancer development. Finally, menopausal symptoms and bone density may be favorably influenced by phytoestrogens. In summary, phytoestrogens, in the form of dietary isoflavones, represent a new area to explore in pursuit of nutritional approaches to cardiovascular protection.

1: Acta Obstet Gynecol Scand 2000 Apr;79(4):250-4

Systemic estrogens have no conclusive beneficial effect on human skin connective tissue.

Oikarinen A
Department of Dermatology, University of Oulu and Oulu University Hospital, Finland.

SUBJECT: Aging of the skin is affected by intrinsic and extrinsic factors. Especially important extrinsic factor is ultraviolet radiation, which causes premature aging of the skin. Intrinsic aging is influenced by genetic factors, and changes in hormones. In menopause, changes in hormonal balance have been suggested to enhance aging of the skin. DISCUSSION: Accordingly, several studies have been accomplished, in which hormone replacement therapy (HRT) has been used in order to prevent skin aging at or after the menopause. In this overview the results of previous studies, and a study done recently, are critically reviewed. CONCLUSION: One year systemic replacement therapy has no beneficial effect on the skin thickness, collagen synthesis, or elastin. Topical estrogens might have some beneficial effects. However, since the number of patients treated with topical estrogens is relatively small, further studies are needed.

1: Acta Obstet Gynecol Scand 2000 Apr;79(4):286-92

Factors associated with climacteric symptoms and the use of hormone replacement therapy.

Stadberg E, Mattsson LA, Milsom I

Department of Obstetrics and Gynecology, Sahlgrenska University Hospital/Ostra Goteborg, Sweden.

BACKGROUND: To investigate factors associated with climacteric symptoms and the use of hormone replacement therapy (HRT). METHODS: A random sample of women aged 46, 50, 54, 58 and 62 years resident in Goteborg, Sweden (n=5,990) were invited by letter to complete a postal questionnaire concerning the menopause and HRT use. RESULTS: The response rate was 76% (n=4,504). Women with a higher education, who exercised regularly and who had regular spare-time activities felt better and had fewer climacteric complaints (p<0.001) compared to lower educated women, women who exercised infrequently and women who had no spare-time activities. Climacteric symptoms were associated with dryness symptoms (dry eyes, skin, hair and mouth), bilateral salpingo-oophorectomy (SOE), use of psychotropical drugs and use of alternative remedies, previous hysterectomy and full-time occupation. Stepwise multiple regression analysis showed significant correlations between vasomotor symptoms and various dryness symptoms, no menstrual periods and use of alternative remedies. Current HRT-users (13%) had used estrogens for 4.0 years and past users (14%) for 4.3 years. A correlation (p<0.005) was found between HRT use and previous use of contraceptive pills, use of alternative remedies and hysterectomy. Education, occupation and the frequency of exercise did not influence the prevalence of HRT use. CONCLUSIONS: This study has shown that the experience of climacteric symptoms and well-being is associated with many different factors. Women with a higher education and those who exercised regularly were more often symptom-free. HRT use was associated with previous use of contraceptive pills, use of alternative remedies and hysterectomy.

Steroids 2000 Apr 1;65(4):171-179

Aromatase inhibitors and their application in breast cancer treatment*.
Brodie AM, Njar VC
Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, 685 West Baltimore Street, Baltimore, MD, USA

Estrogens are known to be important in the growth of breast cancers in both pre- and postmenopausal women. The number of breast cancer patients with hormone-dependent disease increases with age, as does the incidence of breast cancer. Although estrogens are no longer made in the ovaries after menopause, peripheral tissues produce sufficient concentrations to stimulate tumor growth. Because aromatase catalyzes the rate-limiting step in the biosynthesis of estrogen, inhibitors of this enzyme have been developed in the last few years as a logical treatment strategy. Two classes of aromatase inhibitors, steroidal and nonsteroidal compounds, are now in use. Among the steroid substrate analogs, formestane and examestane have been shown to be effective in breast cancer patients with advanced disease. Highly potent and selective nonsteroidal inhibitors have recently been found to suppress plasma and urinary estrogens by more than 95% in breast cancer patients. Two of these compounds recently were approved in the United States and have been shown to be more effective than other second-line agents in terms of overall response rates and treatment failure, as well as better tolerated. Although studies of the efficacy of these agents in earlier stage disease are awaited, it is evident that aromatase inhibitors can extend the duration of treatment in breast cancer patients.

1: Menopause 2000 Mar-Apr;7(2):87-95

Effects of menopause and estrogen replacement therapy or hormone replacement therapy in women with diabetes mellitus: consensus opinion of The North American Menopause Society.

OBJECTIVE: Given that the prevalence of non-insulin-dependent diabetes mellitus (type 2 DM) is increasing in postmenopausal women and type 2 DM substantially increases the risk for cardiovascular events in postmenopausal women, a population that is at higher risk for coronary heart disease, The North American Menopause Society (NAMS) developed a consensus opinion on appropriate management strategies for postmenopausal women who have or who are at risk for developing type 2 DM. DESIGN: NAMS held a closed conference of experts in the field to evaluate the published clinical data on the effects of menopause, type 2 DM, and estrogen or hormone replacement therapy (ERT/HRT) in women, especially the effects on cardiovascular risk factors, and to discuss therapeutic options. The proceedings of the conference were used to assist the NAMS Board of Trustees in developing this consensus opinion. RESULTS: On the basis of the current knowledge, NAMS established consensus on the following issues: (1) Controlling cardiovascular risk factors through pharmacologic and nonpharmacologic means can significantly decrease the risk for developing cardiovascular events. (2) A broad-based recommendation for ERT/HRT cannot be made; rather, the benefits and risks must be weighed in the context of each woman's risk factors. (3) When ERT/HRT is recommended, the greatest benefits may be obtained from the use of transdermal estrogen preparations, low doses of oral estrogens, progesterone instead of progestin, and/or nonandrogen preparations, although more research is needed in this area. (4) Counseling can help maximize the patient's adherence to multiple medication regimens and increase her understanding of the potential benefits and risks of ERT/HRT. CONCLUSIONS: Controlling an individual woman's risk factors for cardiovascular events should be the focus of any management strategy for a postmenopausal woman who has or is at risk for developing type 2 DM.

1: Menopause 2000 Mar-Apr;7(2):76-86

A decision tree for the use of estrogen replacement therapy or hormone replacement therapy in postmenopausal women: consensus opinion of The North American Menopause Society.

OBJECTIVE: Menopause is associated with physiologic changes that may have negative effects on quality of life in some women and/or that may increase morbidity and mortality secondary to osteoporosis and/or coronary heart disease. Estrogen replacement therapy (ERT) and combined estrogen/progestogen therapy (hormone replacement therapy [HRT]) play an important role in reducing these negative effects. The North American Menopause Society (NAMS) sought to develop treatment algorithms that could assist the clinician in deciding whether to recommend ERT/HRT to postmenopausal women. DESIGN: NAMS held a closed conference of experts to develop a decision tree that outlined the rational use of ERT/HRT in postmenopausal women on the basis of risks versus benefits. The proceedings of the conference were used to assist the NAMS Board of Trustees in developing this consensus opinion of the Society. RESULTS: On the basis of the conference proceedings, NAMS developed three algorithms for the clinician to use as a tool in deciding whether to recommend ERT/HRT to a woman who is postmenopausal: (1) menopause-related symptoms, (2) cardiovascular risk, and (3) osteoporosis risk. CONCLUSIONS: The goal of ERT/HRT is to enhance women's quality of life as well as to reduce the risks of death and disability associated with osteoporosis and coronary heart disease. The decision to initiate ERT/HRT must be individualized according to each woman's needs. This decision tree for ERT/HRT presents a rational approach to decision making on the basis of the principles of care; details of specific therapeutic interventions will change as data from clinical trials are presented.

Estrogen effects on postural balance in postmenopausal women without vasomotor symptoms: a randomized masked trial.

Ekblad S, Lonnberg B, Berg G, Odkvist L, Ledin T, Hammar M
Department of Health and Environment, Faculty of Health Sciences, University Hospital of Linkoping, Sweden. matha@gyn.liu.se

OBJECTIVE: To assess whether estrogen treatment given to postmenopausal women without vasomotor symptoms improves balance more than placebo. METHODS: Forty healthy postmenopausal women without vasomotor symptoms were randomized to transdermal 17beta-estradiol (E2) 50 microg/day for 14 weeks or identical transdermal placebo patches. Postural balance was measured with dynamic posturography before and after 4, 12, and 14 weeks of therapy. In this test, the visual, vestibular, and somatosensory systems were provoked with increasing difficulty and body sway was measured with a dual forceplate. A low score showed large sway and a score of 100 showed no sway at all. RESULTS: Thirty-eight women completed the study. Both groups had normal balance for their ages and near maximum scores in the three easier balance tests at baseline. In the most difficult test, both groups improved their postural balance significantly (from 13 to 32 and from 22 to 39, respectively) after 4 weeks. Thereafter, no change was seen. One problem was low statistical power, but the relative change in balance did not differ between groups. The comparison did not show even a minute advantage of E2 over placebo, so a study with higher power would probably not have shown a more pronounced effect of estrogen than placebo. The change over time did not differ between groups, which indicates a significant learning effect. CONCLUSION: In women without vasomotor symptoms, estrogen therapy did not seem to increase postural balance significantly more than placebo. However, we could not rule out that estrogens affect postural balance in women with vasomotor symptoms.

1: Diabetes Metab 2000 Feb;26(1):12-20

Body fat distribution, the menopause transition, and hormone replacement therapy.

Tchernof A, Poehlman ET, Despres JP
Department of Medicine, University of Vermont, Burlington, VT 05401.

Endocrine changes resulting from the menopause transition dramatically modify women's hormonal milieu. The consequences of these changes not only lead to cessation of reproduction and accompanying symptoms in women, but also dramatically impact long-term health. Loss of estrogen has been associated with the development of cardiovascular disease. Central distribution and accumulation of adipose tissue, and the concomitant insulin resistant dyslipidemic state have emerged as important components of a cluster of metabolic abnormalities that are strongly related to coronary heart disease. Thus, estrogen deficiency may affect cardiovascular disease risk by mediating changes in body fat distribution. This article is an update of the literature in the area of menopause, hormone replacement therapy, and body fat distribution. Cross-sectional studies using anthropometric measurements of abdominal fat distribution most often failed to detect an effect of the menopause transition that was independent of advancing age and degree of obesity. The use of radiologic techniques such as DEXA and computed tomography, however, led to the conclusion that the menopause transition accelerates the selective deposition of intra-abdominal fat. Available longitudinal data also support an increase in central body fatness occurring with menopause. Most intervention trials on hormone replacement therapy and body fat distribution showed that the treatment prevented the increase in central adiposity that was noted in postmenopausal women receiving no treatment or placebo. These results are supported by retrospective studies that showed a lower WHR in hormone users vs non-users. Mechanisms potentially explaining the menopause-related acceleration in abdominal fat accumulation include changes in regional adipose tissue metabolism in the face of a positive energy imbalance. As some inconsistencies were found among studies, further investigations using longitudinal and intervention designs, as well as more precise methodologies to measure body fat distribution, are needed to clearly establish the effects of menopause and hormone replacement on abdominal body fat distribution and the concomitant increase in cardiovascular disease risk.

1: Am J Obstet Gynecol 2000 Feb;182(2):277-82

Modulation of the sleep electroencephalogram by estrogen replacement in postmenopausal women.

Antonijevic IA, Stalla GK, Steiger A
Department of Psychiatry, Max Planck Institute of Psychiatry.

OBJECTIVE: We performed an examination of the effects of estrogen replacement on the sleep electroencephalogram in postmenopausal women.Study Design: A sleep electroencephalogram was recorded in 11 postmenopausal women with and without estrogen administered by skin patch (50 &mgr;g of estradiol per day). RESULTS: Estrogen enhanced rapid-eye-movement sleep (50 +/- 4 vs 39 +/- 5 minutes, P <.05) and reduced time awake (12 +/- 5 vs 20 +/- 6 minutes, P <.05) during the first 2 sleep cycles. The normal decrease in slow-wave sleep and delta activity from the first to the second cycle (in percentage from the first cycle) was restored by estrogen (-56% +/- 9% vs -5% +/- 14% and -20% +/- 6% vs -2% +/- 5%; P <.05, respectively). Sigma electroencephalographic activity was increased by estrogen from the first to the second half of the night but decreased during baseline. CONCLUSION: Estrogen treatment after menopause can help to restore the normal sleep electroencephalogram pattern, which in turn might contribute to improved cognitive functioning.

1: Menopause 2000 Jan-Feb;7(1):31-5

Hormone replacement therapy reduces mean 24-hour blood pressure and its variability in postmenopausal women with treated hypertension.

Szekacs B, Vajo Z, Acs N, Hada P, Csuzi L, Bezeredi J, Magyar Z, Brinton EA

2nd Department of Medicine, Semmelweis University, Budapest, Hungary.

BACKGROUND: The rate and severity of hypertension increase dramatically after menopause. Complications seem to be more frequent and marked in hypertensive patients with greater blood pressure (BP) variability, and antihypertensive treatment does not easily reduce this variability. The effect of hormone replacement therapy (HRT) on BP and its variability is not well understood in moderate to severe hypertension, but estrogen may have calcium channel-blocking properties. Cardiovascular events occur more frequently in the morning, likely in part because of a rise in BP. DESIGN: We prospectively studied 34 postmenopausal women with treated hypertension (mean age = 53 years) and receiving a cyclic combination of estradiol and norgestrel for 19 weeks with 24-h ambulatory BP monitoring. RESULTS: Mean daily BP and its variability decreased significantly with HRT (149.3 +/- 6.1 mm Hg vs. 140.3 +/- 8.5 mm Hg [p < 0.001]; diastolic: 95.4 +/- 4.7 mm Hg vs. 92.4 +/- 7.2 mm Hg [p < 0.05]). There was also a significant decrease in the early morning BP values after HRT (154.0 +/- 6.9 mm Hg vs. 145.6 +/- 11.0 mm Hg [p < 0.001]; diastolic: 98.0 +/- 4.8 mm Hg vs. 95.1 +/- 10.0 mm Hg [p < 0.05]). Subjects who were taking calcium channel blockers (n = 11) had only half the reduction in 24-h systolic BP compared with those who were not taking calcium channel blockers (5.3 mm Hg vs. 10.5 mm Hg), and the reduction in those who were taking calcium channel blockers failed to reach statistical significance. CONCLUSIONS: Our results demonstrate that HRT may have a role in decreasing the severity of hypertension, and the mechanism of its action might be through calcium channels.

Sao Paulo Med J 2000 Jan;118(1):3-6

Effect of hormone replacement therapy on the bone mass and urinary excretion of pyridinium cross-links.

Pardini DP, Sabino AT, Meneses AM, Kasamatsu T, Vieira JG
Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, Brazil.

CONTEXT: The menopause accelerates bone loss and is associated with an increased bone turnover. Bone formation may be evaluated by several biochemical markers. However, the establishment of an accurate marker for bone resorption has been more difficult to achieve. OBJECTIVE: To study the effect of hormone replacement therapy (HRT) on bone mass and on the markers of bone resorption: urinary excretion of pyridinoline and deoxypyridinoline. DESIGN: Cohort correlational study. SETTING: Academic referral center. SAMPLE: 53 post-menopausal women, aged 48-58 years. MAIN MEASUREMENTS: Urinary pyr and d-pyr were measured in fasting urine samples by spectrofluorometry after high performance liquid chromatography and corrected for creatinine excretion measured before treatment and after 1, 2, 4 and 12 months. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DEXA) before treatment and after 12 months of HRT. RESULTS: The BMD after HRT was about 4.7% (P < 0.0004); 2% (P < 0.002); and 3% (P < 0.01) higher than the basal values in lumbar spine, neck and trochanter respectively. There were no significant correlations between pyridinium cross-links and age, weight, menopause duration and BMD. The decrease in pyr and d-pyr was progressive after HRT, reaching 28.9% (P < 0.0002), and 42% (P < 0.0002) respectively after 1 year. CONCLUSIONS: Urinary pyridinoline and deoxypyridinoline excretion decreases early in hormone replacement therapy, reflecting a decrease in the bone resorption rate, and no correlation was observed with the bone mass evaluated by densitometry.

Effects of hormone replacement therapy on lipid peroxides and oxidation system in postmenopausal women.

Akcay T, Dincer Y, Kayali R, Colgar U, Oral E, Cakatay U

Biochemistry Department, Cerrahpasa Medical Faculty, University of Istanbul, Turkey.

A short-term evaluation of 6 months of estrogen therapy on oxidant status in 38 postmenopausal women was conducted. The levels of serum lipid peroxidation products, glutathione (GSH) status, and glutathione-related enzymes were evaluated before and after 6 months of hormone replacement therapy. After 6 months of estrogen treatment there was a significantly increased concentration of thiobarbituric acid-reactive substances (TBARS), which are an end product of lipid peroxidation. This was accompanied by a significant increase in the activity of glutathione peroxidase (GSH-Px). However, the activities of glutathione reductase (GSSG-R) and superoxide dismutase (SOD) were significantly decreased and total protein thiols were reduced. Data suggest that hormone replacement therapy in postmenopausal women is associated with oxidant mechanisms. Publication Types: Clinical trial

1: Sports Med 2000 Jan;29(1):39-49

The effect of hormone replacement therapy and exercise on cardiovascular disease risk factors in postmenopausal women.

Haddock BL, Marshak HP, Mason JJ, Blix G

School of Public Health, Loma Linda University, California 92350, USA. bHaddock@sph.llu.edu

Following menopause, women show an increased risk of heart disease to a level equal that of men. This elevated risk is thought to be due, at least partly, to changes in blood lipid and fibrinogen levels. The purpose of this article is to review the published research on the relationship between both exercise and hormone replacement with regards to common cardiovascular disease (CVD) risk factors and the relative importance of each. Menopause is associated with increased total serum cholesterol, triglycerides and fibrinogen, and a decrease in high density lipoprotein (HDL) cholesterol levels. The major reason for these changes following menopause is believed to be a result of fluctuations in hormonal status, primarily a deficiency in estrogen. Intervention may be justified since estrogen replacement therapy has been shown to decrease the risk of developing CVD and to have a significant impact on many of the CVD risk factors. The results vary from study to study, but generally estrogen replacement has been found to decrease total cholesterol and fibrinogen, while increasing HDL cholesterol and triglycerides. All of these changes, other than the increase in triglycerides, are seen as positive. The addition of progestogen to estrogen may negate some of the beneficial changes of estrogen, most notably the increase in HDL cholesterol levels. However, progestogen has also been reported to offset the increase in triglycerides seen with unopposed estrogen replacement. Thus, there are contradictory effects (both positive and negative) of hormone replacement on CVD risk factors in women. Regular aerobic exercise and resulting improvements in cardiorespiratory fitness have consistently been shown as preventive of CVD. This decreased CVD risk is in part because of the impact of exercise on blood lipids and fibrinogen. Increased aerobic exercise is thought to improve the risk profile, mainly through an increase in HDL cholesterol levels and decreases in triglycerides and fibrinogen. Unfortunately, the majority of research supporting the effects of exercise on CVD risk factors has been done on men. Even when research has included women, very few studies have focused on postmenopausal women. However, the research done on postmenopausal women points to a significantly improved CVD risk factor profile with regular cardiorespiratory exercise.

The effect of hormone replacement therapy on metabolism of lipoprotein remnants in postmenopausal women.

Sanada M, Nakagawa H, Kodama I, Sakasita T, Ohama K
Department of Obstetrics and Gynecology, School of Medicine, Faculty of Medicine, Hiroshima University, Japan.

OBJECTIVE: The measurement of remnant-like particles reflects chylomicron and very low density lipoprotein remnants which are most likely atherogenic particles. We investigated the effects of menopausal status and postmenopausal hormone replacement on metabolism of remnant lipoprotein-cholesterol. METHODS: We measured remnant lipoprotein-cholesterol by an immunoseparation assay in 20 premenopausal, 40 postmenopausal, and 30 bilaterally oophorectomized women. Of 70 postmenopausal subjects, 21 surgically menopausal women (with total hysterectomy) were started on hormone replacement with conjugated equine estrogen, 0.625 mg/day, and 36 naturally postmenopausal women were begun on a combination of conjugated equine estrogen 0.625 mg/day, plus medroxyprogesterone acetate, 2.5 mg/day. Plasma levels of remnant lipoprotein-cholesterol and other common lipids were measured after 6 and 12 months of treatment. RESULTS: Plasma remnant lipoprotein-cholesterol levels in postmenopausal and surgically menopausal women were significantly higher than in premenopausal women (P < 0.005). Plasma total and low-density lipoprotein cholesterol levels decreased and high-density lipoprotein cholesterol increased significantly (P < 0.01) in both treatment groups, respectively. Plasma triglyceride levels were not changed by treatment; however, remnant lipoprotein-cholesterol levels decreased in both treatment groups (estrogen group; P = 0.07, estrogen-progestin group; P < 0.05). No side effects of therapy were consistently reported. CONCLUSIONS: We confirmed that remnant lipoprotein-cholesterol increases after menopause. Hormone replacement therapy improves disordered lipoprotein metabolism and exerts a favorable effect on lipoprotein remnant metabolism in postmenopausal women.

1: J Clin Endocrinol Metab 2000 Jan;85(1):214-8

The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial.

Walsh BW, Paul S, Wild RA, Dean RA, Tracy RP, Cox DA, Anderson PW
Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. bwwalsh@bics.bwh.harvard.edu

C-Reactive protein and homocysteine are independent risk factors for the development of cardiovascular disease. This study compared the effects of hormone replacement therapy (HRT) and raloxifene on serum C-reactive protein and homocysteine levels as markers of cardiovascular risk in healthy postmenopausal women. Healthy postmenopausal women (n = 390) were enrolled in a double blind, randomized, placebo-controlled, 6-month trial at eight out-patient sites in the United States. Women were randomly assigned to receive continuous combined HRT (0.625 mg/day conjugated equine estrogen and 2.5 mg/day medroxyprogesterone acetate), raloxifene (60 or 120 mg/day), or placebo for 6 months. C-Reactive protein and homocysteine were measured in baseline and 6-month serum samples. HRT increased C-reactive protein levels by 84% (P<0.001), whereas raloxifene (60 and 120 mg/day) had no significant effect (-6% and -4%;, respectively; P>0.2). Raloxifene (60 and 120 mg/day) significantly lowered serum levels ofhomocysteine by 8% (P = 0.014) and 6% (P = 0.024), respectively, similar to the 7% (P = 0.014) reduction obtained with HRT. We conclude that HRT and raloxifene lower serum homocysteine levels to a comparable extent in postmenopausal women. Whereas cardiovascular risk predicted by C-reactive protein in healthy postmenopausal women is not influenced by raloxifene, the relationship between elevated C-reactive protein levels with HRT and cardiovascular disease events requires further study.

Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk.

Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R
National Cancer Institute, Division of Cancer Epidemiology and Genetics, Rockville, MD 20852-7234, USA. schairec@exchange.nih.gov

CONTEXT: Whether menopausal hormone replacement therapy using a combined estrogen-progestin regimen increases risk of breast cancer beyond that associated with estrogen alone is unknown.
OBJECTIVE: To determine whether increases in risk associated with the estrogen-progestin regimen are greater than those associated with estrogen alone.
DESIGN: Cohort study of follow-up data for 1980-1995 from the Breast Cancer Detection Demonstration Project, a nationwide breast cancer screening program.
SETTING: Twenty-nine screening centers throughout the United States.
PARTICIPANTS: A total of 46355 postmenopausal women (mean age at start of follow-up, 58 years).
MAIN OUTCOME MEASURE: Incident breast cancers by recency, duration, and type of hormone use.
RESULTS: During follow-up, 2082 cases of breast cancer were identified. Increases in risk with estrogen only and estrogen-progestin only were restricted to use within the previous 4 years (relative risk [RR], 1.2 [95% confidence interval [CI], 1.0-1.4] and 1.4 [95% CI, 1.1-1.8], respectively); the relative risk increased by 0.01 (95% CI, 0.002-0.03) with each year of estrogen-only use and by 0.08 (95% CI, 0.02-0.16) with each year of estrogen-progestin-only use among recent users, after adjustment for mammographic screening, age at menopause, body mass index (BMI), education, and age. The P value associated with the test of homogeneity of these estimates was .02. Among women with a BMI of 24.4 kg/m2 or less, increases in RR with each year of estrogen-only use and estrogen-progestin-only use among recent users were 0.03 (95% CI, 0.01-0.06) and 0.12 (95% CI, 0.02-0.25), respectively. These associations were evident for the majority of invasive tumors with ductal histology and regardless of extent of invasive disease. Risk in heavier women did not increase with use of estrogen only or estrogen-progestin only.
CONCLUSION: Our data suggest that the estrogen-progestin regimen increases breast cancer risk beyond that associated with estrogen alone.

1: Am J Obstet Gynecol 2000 Jan;182(1 Pt 1):17-22

Cardiovascular responses of perimenopausal women to hormonal replacement therapy.
Kamali P, Muller T, Lang U, Clapp JF 3rd
Department of Obstetrics and Gynecology, Frauenklinik der Justus-Liebig-Universitaet Giessen, Germany.

OBJECTIVE: This study was undertake to test the hypothesis that hormone replacement therapy alters cardiovascular function during the first several months of therapy.
STUDY DESIGN: Serial estimates of blood pressure, heart rate, stroke volume, and venous capacitance were obtained before and at 1, 5, 9, and 21 weeks after the beginning of hormone replacement therapy with daily estradiol and intermittent norethindrone. Measurements were performed by means of electrocardiography, automated blood pressure measurement (Dynamap; Critikon Company LLC, Tampa, Fla), echocardiography, and plethysmography.
RESULTS: Hormone replacement therapy did not alter heart rate, blood pressure, or venous capacitance. End-diastolic volume and stroke volume were unchanged after 1 week of hormone replacement therapy but rose thereafter. After 5 weeks of hormone replacement end-diastolic volume and stroke volume were increased by 13 +/- 5 mL and 9 +/- 2 mL, respectively, and after 9 weeks the increases totaled 23 +/- 5 mL and 17 +/- 3 mL, respectively. As a result cardiac output rose progressively to a level 1.1 +/- 0.3 L/min (18%) greater than pretreatment values and systemic vascular resistance fell 15%. These changes were associated with a 3-fold increase in serum estradiol levels.
CONCLUSION: The studied regimen of hormone replacement therapy produces progressive cardiac remodeling and peripheral vasodilatation during the first 2 months of therapy.

1: Obstet Gynecol 2000 Jan;95(1):104-10

Uterine effects of 3-year raloxifene therapy in postmenopausal women younger than age 60.

Cohen FJ, Watts S, Shah A, Akers R, Plouffe L Jr

Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana 46285, USA.

OBJECTIVE: To assess the uterine effects of 3 years of therapy with raloxifene in healthy, postmenopausal women under age 60. METHODS: Integrated data from two identically designed, randomized, double-masked, placebo-controlled clinical trials were analyzed. Nine hundred sixty-nine healthy women with uteri (ages 45 through 60, 2 to 8 years postmenopausal) were assigned randomly to raloxifene 30, 60, or 150 mg per day, or an identical placebo for 3 years. Endometrial thickness was evaluated with transvaginal ultrasonography every 6 months for 2 years and again after 3 years. Further uterine evaluation, including endometrial sampling if necessary, was initiated for vaginal bleeding or findings of endometrial thickness greater than 5 mm. RESULTS: Endometrial thickness was unchanged by raloxifene and not significantly different from placebo at any time. One hundred seventy-two women had at least one episode of endometrial thickness greater than 5 mm or vaginal bleeding distributed equally among all groups. A total of 102 (10.5%) women underwent endometrial sampling at least once: 15 (1.5%) for vaginal bleeding, 78 (8.0%) for endometrial thickness greater than 5 mm, and nine (0.9%) for other reasons. There were no significant treatment differences in the proportion of women sampled, in the clinical findings, or in the histologic diagnoses. CONCLUSION: Raloxifene given to healthy postmenopausal women at doses from 30 to 150 mg per day does not stimulate uterine growth and does not cause vaginal bleeding, spotting, or discharge through 3 years of therapy. Thus, any bleeding during therapy should be deemed unexpected and prompt a clinical evaluation.

1: Thromb Haemost 2000 Jan;83(1):29-34

Impaired procoagulant-anticoagulant balance during hormone replacement therapy? A randomised, placebo-controlled 12-week study.

van Baal WM, Emeis JJ, van der Mooren MJ, Kessel H, Kenemans P, Stehouwer CD Department of Obstetrics & Gynaecology, University Hospital Vrije

Universiteit, Amsterdam, The Netherlands. In this randomised, placebo-controlled 12-week study, sixty healthy postmenopausal women received either placebo (N = 16) or daily 2 mg micronised oestradiol, either unopposed (N = 16, E2 group) or combined with a progestagen for 14 days of each cycle (N = 28, E2+P group). RESULTS: As compared to placebo, plasma levels of AT III were reduced only in the E2 group (approximately 28%), plasma levels of protein C decreased only in the E2+P group (approximately 4%) and plasma levels of protein S decreased in both the E2 and E2+P group (approximately 21%). In both the E2 and E2+P groups, the plasma levels of factor VII (antigen and activity) showed a borderline significant increase (approximately 10%), whereas no significant change was observed in active factor VII. Plasma levels of tissue-type plasminogen activator (approximately 22%), urokinase plasminogen activator (approximately 25%) and plasminogen activator inhibitor type-1 (approximately 43%) decreased in the E2 and E2+P groups, whereas those of plasminogen increased (approximately 12%). Treatment was associated with an increase in levels of prothrombin fragment 1+2 (approximately 31%), but levels of thrombin-antithrombin III complexes, and of plasmin-alpha2-antiplasmin complexes and total fibrin(ogen) degradation products did not change significantly. CONCLUSION: Short-term E2 and E2+P treatment is associated with a shift in the procoagulant-anticoagulant balance towards a procoagulant state. A substantial proportion of women do not have a net increase in fibrinolytic activity. These data may be relevant in explaining the increased risk of venous thromboembolism associated with ERT and HRT, and possibly also in explaining the negative results of the Heart and Estrogen/progestin Replacemen Study.

1: Am J Obstet Gynecol 2000 Jan;182(1 Pt 1):7-12

Efficacy of continuous sequential transdermal estradiol and norethindrone acetate in relieving vasomotor symptoms associated with menopause.
Notelovitz M, Cassel D, Hille D, Furst KW, Dain MP, VandePol C, Skarinsky D

Women's Health Center and Rhone-Poulenc Rorer Pharmaceuticals Inc, Colllegeville, PA, USA. OBJECTIVE: This study was undertaken to evaluate the efficacy and tolerability of a combination estradiol plus norethindrone acetate transdermal delivery system given in a continuous sequential regimen with transdermal estradiol versus placebo in the treatment of vasomotor symptoms of menopause. STUDY DESIGN: This was a 12-week double-blind trial of 220 healthy postmenopausal women with > or = 8 moderate to severe hot flushes and sweating episodes per day. Women were randomly assigned to wear transdermal placebo patches or a transdermal patch releasing 50 microg/d 17beta-estradiol alone (Vivelle) for days 1 to 14 of each cycle and a combination patch releasing 50 microg/d 17beta-estradiol plus 1 of 3 dosage levels (140, 250, or 400 microg/d) of norethindrone acetate (CombiPatch) for days 15 through 28. RESULTS: There was a significant (P <.001) reduction by the second week in the mean number of daily hot flushes from baseline to end point with all 3 doses of estradiol plus norethindrone acetate compared with placebo. Significant (P <.001) reductions in the mean intensity of hot flushes and sweating were also noted with estradiol plus norethindrone acetate compared with placebo. The incidences of adverse events with all 3 doses of estradiol plus norethindrone acetate and with placebo were comparable. CONCLUSION: An estradiol plus norethindrone acetate transdermal delivery system administered in a continuous sequential regimen with transdermal estradiol was well tolerated and effective for the treatment of moderate to severe vasomotor symptoms in postmenopausal women.

1: Fertil Steril 2000 Jan;73(1):66-71

Effects of a single dose of oral estrogen on left ventricular diastolic function in hypertensive postmenopausal women with diastolic dysfunction.

Fak AS, Erenus M, Tezcan H, Caymaz O, Oktay S, Oktay A Department of Cardiology, Marmara University Medical School, Istanbul, Turkey.

OBJECTIVE: To evaluate the acute effects of a single dose of oral estrogen on left ventricular diastolic function in hypertensive postmenopausal women with diastolic dysfunction. DESIGN: Prospective, double-blind, placebo-controlled, clinical study.
SETTING: Cardiology and postmenopausal outpatient clinics of a university hospital.
PATIENT(S): Thirty postmenopausal women with hypertension (diastolic blood pressure of >90 mm Hg) and left ventricular diastolic dysfunction (mitral E/A ratio [the ratio of peak velocity of early mitral diastolic filling to late diastolic filling] of <1 and isovolumic relaxation time of >100 ms) were included in the study. Thirty normotensive postmenopausal women with normal left ventricular diastolic function served as the control group.
INTERVENTION(S): Conjugated equine estrogen (0.625 mg) was given orally. Left ventricular diastolic function was assessed by Doppler echocardiography at baseline and 3 hours after the administration of estrogen.
MAIN OUTCOME MEASURE(S): Left ventricular diastolic filling as assessed by Doppler echocardiography.
RESULT(S): Estrogen had no effect on heart rate or blood pressure in either study group. The baseline E/A ratios were 0.72 +/- 0.26 and 1.22 +/- 0.30, and the isovolumic relaxation times were 122 +/- 18 ms and 89 +/-14 ms in the hypertensive and normotensive groups, respectively. Estrogen had no significant effect on any of the Doppler parameters in the normotensive group. In the hypertensive group, there was a trend toward normalization of the E/A ratio (from 0.73 +/- 0.11 to 0.84 +/- 20) and a significant improvement in the isovolumic relaxation time (from 124 +/- 20 ms to 105 +/- 13 ms) in response to the administration of estrogen compared with placebo.
CONCLUSION(S): A single dose of oral estrogen caused a significant improvement in left ventricular diastolic filling in hypertensive postmenopausal women with diastolic dysfunction.

1: Adv Intern Med 2000;45:259-78

Selective estrogen receptor modulators and postmenopausal health.
Roe EB, Chiu KM, Arnaud CD

University of California, Department of Medicine, San Francisco, USA.
SERMs are a class of drugs with mixed estrogen agonist/antagonist effects that have great potential at targeting changes seen in the postmenopausal period. Raloxifene is effective in preventing bone loss and may prevent fractures in postmenopausal osteoporosis. It induces changes in lipoprotein concentrations that should be cardioprotective. It has no stimulatory effect on the uterus and is well tolerated. Raloxifene is an attractive alternative to HRT in preventing postmenopausal bone loss, especially for women that are more concerned about the risk of breast cancer or vaginal bleeding. Unanswered questions include raloxifene's effect on fracture incidence, cardiac events, and dementia; long-term safety data are also needed. Its potential role in the primary prevention of breast cancer also needs large, long-term studies. Tamoxifen has been used traditionally as adjuvant therapy for breast cancer, but new data indicate that it is effective in the primary prevention of breast cancer in women at increased risk. Its effects on bone and lipoproteins are attractive complementary effects when used in the subset of women at increased risk for breast cancer. New generations of SERMs are being developed that may have more potent estrogen agonist effects on bone and cardiovascular disease, or more potent antiestrogen effects, especially at the breast. There will likely be a selection of SERMs available, and the choice of SERM for a woman will be tailored to her specific issues and risk profile.

1: Maturitas 1999 Dec 15;33(3):191-6

Postmenopausal hormone replacement in the woman with a reproductive risk factor for breast cancer.

Scheele F, Burger CW, Kenemans P
Department of Obstetrics and Gynaecology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands.

OBJECTIVE: to assess the interaction between postmenopausal hormone replacement therapy (HRT) and various reproductive risk factors for breast cancer such as early menarche, late menopause, late first delivery and nulliparity.
DESIGN: three cohort studies and fourteen case control studies, published between 1975 and 1997, provided relative risks (RRs) of HRT use in women with, as well as in those without, a reproductive risk factor for breast cancer.
METHODS: using an additive RR model reported before, we investigated whether the RR for breast cancer in women with a combination of HRT and a given reproductive risk factor result from a simple addition of RRs of HRT on the one hand, and of the pre-existing reproductive risk factor on the other hand, or that synergism between both risk factors occurs.
RESULTS: simple addition of RRs was shown in the case of early menarche and late menopause. Less increase of risk, suggesting antagonism, was found for both late first delivery and nulliparity in combination with HRT use.
CONCLUSION: we could not observe any synergistic effect of the combined risks of any of the following reproductive risk factors for breast cancer: early menarche, late menopause, late first delivery or nulliparity on the one hand, with the risk resulting from HRT use on the other hand. Therefore, as far as the risk of breast cancer is concerned, the use of HRT appears not to be highly detrimental in women with a reproductive breast cancer risk factor, as it results in not more than a simple addition of risks at the most.

1: J Reprod Med 1999 Dec;44(12):1012-20

A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women. Effects on bone mineral density, symptoms and lipid profiles.

Barrett-Connor E, Young R, Notelovitz M, Sullivan J, Wiita B, Yang HM, Nolan J
Department of Family and Preventive Medicine, University of California, San Diego, School of Medicine, La Jolla 92093-0607, USA.

OBJECTIVE: To compare the effects of two doses of conjugated equine estrogen (CEE) and two of esterified estrogen plus methyltestosterone (E + A) in surgically menopausal women.
STUDY DESIGN: A two-year, parallel-group, double-blind study of 311 women who were randomly assigned to one of four regimens: (1) CEE, 0.625 mg/d; (2) CEE, 1.25 mg/d; (3) esterified estrogens, 0.625 mg, + methyltestosterone, 1.25 mg/d; or (4) esterified estrogens, 1.25, + methyltestosterone, 2.5 mg/d. Study parameters were symptoms, lipids, bone mineral density, side effects and safety.
RESULTS: All treatments prevented loss of bone in the spine and hip. The higher E + A dose increased spine and hip BMD more than other treatments (P < .002). All treatments improved menopausal symptoms, with non-significantly greater improvements in well-being and sexual interest in the E + A groups. Similar and significant decreases in low-density lipoprotein were observed in all groups, but high-density lipoprotein and triglycerides were increased only in the unopposed estrogen groups (P < .05). Hirsutism was uncommon and similar in all groups at two years. Discontinuation rates and reasons for withdrawal from the study were similar in both groups. No clinically significant side effects or laboratory test abnormalities were seen.
CONCLUSION: As compared to estrogen alone, E + A significantly improved BMD and was well tolerated in surgically menopausal women.

1: J Reprod Med 1999 Dec;44(12):1012-20

A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women. Effects on bone mineral density, symptoms and lipid profiles.

Barrett-Connor E, Young R, Notelovitz M, Sullivan J, Wiita B, Yang HM, Nolan J
Department of Family and Preventive Medicine, University of California, San Diego, School of Medicine, La Jolla 92093-0607, USA.

OBJECTIVE: To compare the effects of two doses of conjugated equine estrogen (CEE) and two of esterified estrogen plus methyltestosterone (E + A) in surgically menopausal women. STUDY DESIGN: A two-year, parallel-group, double-blind study of 311 women who were randomly assigned to one of four regimens: (1) CEE, 0.625 mg/d; (2) CEE, 1.25 mg/d; (3) esterified estrogens, 0.625 mg, + methyltestosterone, 1.25 mg/d; or (4) esterified estrogens, 1.25, + methyltestosterone, 2.5 mg/d. Study parameters were symptoms, lipids, bone mineral density, side effects and safety. RESULTS: All treatments prevented loss of bone in the spine and hip. The higher E + A dose increased spine and hip BMD more than other treatments (P < .002). All treatments improved menopausal symptoms, with non-significantly greater improvements in well-being and sexual interest in the E + A groups. Similar and significant decreases in low-density lipoprotein were observed in all groups, but high-density lipoprotein and triglycerides were increased only in the unopposed estrogen groups (P < .05). Hirsutism was uncommon and similar in all groups at two years. Discontinuation rates and reasons for withdrawal from the study were similar in both groups. No clinically significant side effects or laboratory test abnormalities were seen. CONCLUSION: As compared to estrogen alone, E + A significantly improved BMD and was well tolerated in surgically menopausal women.

1: Maturitas 1999 Dec 15;33(3):259-69

Effects of menopause and hormone replacement therapy on plasma lipids, lipoproteins and LDL-receptor activity.

Abbey M, Owen A, Suzakawa M, Roach P, Nestel PJ
Commonwealth Scientific and Industrial Research Organisation, Human Nutrition, Adelaide BC, SA, Australia. mavis.abbey@dhn.csiro.au

A cross-sectional study of ninety six women was conducted to examine the effect of menopause and hormone replacement therapy (HRT) on plasma lipids, lipoproteins and oxidation of low density lipoproteins. The sample consisted of 26 premenopausal women, 26 postmenopausal women taking no replacement hormones and 43 postmenopausal women on hormone replacement therapy. Postmenopausal women not taking replacement hormones had significantly higher plasma cholesterol, low density lipoprotein (LDL) cholesterol and lipoprotein[a] (Lp[a]) levels compared to premenopausal women or postmenopausal women on HRT [6.00 +/- 0.15, 5.36 +/- 0.17 (P < 0.01), 5.63 +/- 0.13 (P < 0.05) mmol/l, respectively for total cholesterol; 4.13 +/- 0.15, 3.64 +/- 0.15 (P < 0.05), 3.82 +/- 0.12 (P < 0.05) mmol/l, respectively for LDL-cholesterol; 48.19 +/- 9.90, 26.59 +/- 5.53 (P < 0.03), 25.12 +/- 4.62 (P < 0.03) mg/dl, respectively for Lp[a]]. The differences in LDL cholesterol concentrations were inversely related to changes in LDL receptor activity (r = -0.27, P < 0.01). HRT use was found to be associated with a significantly smaller LDL particle size. Plasma triglyceride was significantly higher in women on HRT (1.16 +/- 0.07 mmol/l) than in the premenopausal group (0.96 +/- 0.07) or postmenopausal group not using HRT (0.87 +/- 0.06). There were no differences in LDL oxidation between the groups when LDL was oxidised in the presence of copper. Nor was there any difference in the uptake of copper-oxidised or macrophage-modified LDL into J774 macrophages. These results confirm the effect of menopause and exogenous hormones on plasma lipids and lipoproteins, and suggest that HRT modifies the activity of the LDL receptor. Hormone replacement did not appear to protect LDL from oxidation.

1: J Womens Health Gend Based Med 1999 Dec;8(10):1273-9

Effect of age on the exercise response in normal postmenopausal women during estrogen replacement therapy.

Seminario NA, Sciacca RR, DiTullio MR, Homma S, Giardina EG
Center for Women's Health, Department of Medicine, College of Physicians &
Surgeons, Columbia University, New York, New York, USA.

Postmenopausal estrogen replacement therapy (ERT) has been associated with a reduced risk of coronary artery disease (CAD). Whether this apparent cardioprotective effect is mediated by a cardiovascular benefit during exercise, however, has not been clearly defined. To evaluate rest and exercise variables with and without ERT, a randomized crossover trial was conducted in 23 postmenopausal women, ranging in age from 44 to 75 years, mean age 57+/-8 years. The rest and exercise variables were compared on ERT and during a drug-free period. The baseline measure was compared to the effects after 4 weeks of ERT and after 4 drug-free weeks. Echocardiographic treadmill exercise variables of heart rate (HR), blood pressure, rate-pressure product (RPP), and cardiac dimensions were determined at baseline and at the end of each treatment period. In response to ERT, there was a decrease in low-density lipoprotein (LDL) cholesterol (drug-free: 142+/-40 mg/dl, ERT: 124+/-34 mg/dl) and an increase in high-density lipoprotein (HDL) cholesterol (drug-free: 52+/-14 mg/dl, ERT: 62+/-15 mg/dl, both p<0.01). At rest, the study population had no overall significant change in HR, blood pressure, RPP, or left ventricular end-systolic and end-diastolic diameters when ERT was compared to the drug-free period. However, subjects with the fastest baseline resting HR had the greatest decrease in HR with ERT relative to the drug-free period (p<0.05). During exercise, ERT effected no change in peak HR, blood pressure, or RPP, although end-systolic diameter decreased slightly (p<0.05). With ERT, subject age correlated negatively with systolic blood pressure (p<0.05) and RPP (p<0.01); both blood pressure and RPP decreased in older subjects. In conclusion, ERT has differential effects dependent on baseline HR and age.

The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study.

Ruml LA, Sakhaee K, Peterson R, Adams-Huet B, Pak CY. University of Texas Southwestern Medical School, Center for Mineral Metabolism and Clinical Research, Dallas, TX, USA.

This placebo-controlled randomized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal (five years after menopause) and six of whom were mid-postmenopausal (five to ten years after menopause). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause (3.3 in the calcium citrate group vs 2.7 in the placebo group), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment (+1.03% after two years), whereas it declined significantly by -2.38% after two years on placebo (P <.001). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group (-0.02% after two years), but it declined significantly in the placebo group (-1.79% after one year and -3.03% after two years, P <.01). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation (400 mg of calcium twice daily) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression

1: Maturitas 1999 Nov;33 Suppl 1:S57-63

Moderation of the daily dose of HRT: prevention of osteoporosis.

Gallagher JC

Creighton University Medical School, Omaha, NE, USA.

INTRODUCTION AND METHODS: Osteoporosis is the most common bone disease in clinical practice. Between 30% and 50% of postmenopausal women and almost 50% of all people over the age of 75 are estimated to have osteoporosis. HRT is well known for reducing the risk of osteoporosis in postmenopausal women but compliance with long-term HRT therapy remains low. The use of low dose HRT reduces the estrogenic adverse events which often cause patients to stop therapy. In this paper, the current literature on the benefits of low dose HRT and osteoporosis prevention are reviewed.
RESULTS: Various studies have assessed the efficacy of low-dose HRT (25 mcg/day transdermally; 0.3 mg/day orally) in the prevention of osteoporosis. Low dose HRT is effective at reducing bone loss in postmenopausal and oophorectomised women. In one study of 218 postmenopausal women, a dose of 0.3 mg/day of esterified estrogen resulted in a small but significant increase in whole body BMD compared to a decrease in the placebo group. The addition of calcium supplements may have a synergistic effect on the reduction of bone loss.
CONCLUSION: Low dose estrogen, taken either orally or transdermally, can prevent or reverse postmenopausal bone loss and appears to be a useful alternative to higher dosages in the prevention and treatment of osteoporosis. The option of starting HRT at low dose gives physicians the ability to titrate doses to suit individual patients whilst ensuring adequate bone protection and the minimum of hyperestrogenic side effects.

1: Maturitas 1999 Nov;33 Suppl 1:S1-13

Current perspectives on the benefits of HRT in menopausal women.

Palacios S
Institute Palacios, Madrid, Spain.

AIMS: Women in the West can now expect to live one third of their life in a postmenopausal state, and consequently in a state of estrogen deficiency. This can have a number of consequences, and many women suffer vasomotor symptoms during the climacteric. Estrogen deficiency can also result in changes to the skin, hair, urogenital, cardiovascular and skeletal systems. This article reviews some of the main actions of replacement estrogen in postmenopausal women, and discusses the major benefits of estrogen replacement therapy (ERT) and hormone replacement therapy (HRT). REVIEW: HRT is well documented to reduce vasomotor symptoms in women suffering from estrogen deficiency, and can have beneficial effects on the skin and the prevention of skin aging. HRT has beneficial effects on urogenitary function including reductions in urinary incontinence and vaginal atrophy. HRT is used as a first-line treatment to prevent or reverse the development of postmenopausal osteoporosis and can reduce the risk of fractures if taken for 5-10 years from the menopause. In epidemiological studies, ERT was associated with a reduction in the risk of coronary heart disease. Estrogens seem to affect the cardiovascular system directly and indirectly such as reducing some of the coronary risk factors. In recent years, estrogen has been linked to beneficial effects in the CNS including an association with a reduction in the risk of developing Alzheimer's Disease. Despite these benefits, HRT compliance remains low, and physicians need to address this if patients are to gain the benefits.

1: Maturitas 1999 Nov;33 Suppl 1:S57-63

Moderation of the daily dose of HRT: prevention of osteoporosis.

Gallagher JC

Creighton University Medical School, Omaha, NE, USA.

INTRODUCTION AND METHODS: Osteoporosis is the most common bone disease in clinical practice. Between 30% and 50% of postmenopausal women and almost 50% of all people over the age of 75 are estimated to have osteoporosis. HRT is well known for reducing the risk of osteoporosis in postmenopausal women but compliance with long-term HRT therapy remains low. The use of low dose HRT reduces the estrogenic adverse events which often cause patients to stop therapy. In this paper, the current literature on the benefits of low dose HRT and osteoporosis prevention are reviewed. RESULTS: Various studies have assessed the efficacy of low-dose HRT (25 mcg/day transdermally; 0.3 mg/day orally) in the prevention of osteoporosis. Low dose HRT is effective at reducing bone loss in postmenopausal and oophorectomised women. In one study of 218 postmenopausal women, a dose of 0.3 mg/day of esterified estrogen resulted in a small but significant increase in whole body BMD compared to a decrease in the placebo group. The addition of calcium supplements may have a synergistic effect on the reduction of bone loss. CONCLUSION: Low dose estrogen, taken either orally or transdermally, can prevent or reverse postmenopausal bone loss and appears to be a useful alternative to higher dosages in the prevention and treatment of osteoporosis. The option of starting HRT at low dose gives physicians the ability to titrate doses to suit individual patients whilst ensuring adequate bone protection and the minimum of hyperestrogenic side effects.