Premarin ()

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Premarin and Cenestin are the brand names for a tablet of conjugated estrogens. It is used as an estrogen-replacement therapy in various cases. The estrogens are obtained from either a natural source, pregnant mares’ urine, or from synthetic forms of estrogen. It is used commonly by women in the menopausal period to make up for the estrogen deficiency which has potential bad symptoms. Hot flashes, vaginal dryness and irritation are relieved when using Premarin. Estrogen-replacement therapy is also an effective aid in teenagers who fail to mature at the expected time, as well as in other conditions caused by estrogen deficiency. Such include cases when a woman’s ovaries have been surgically removed and cases of breast and prostate cancer. Recently there has been evidence that Premarin is beneficial in the prevention of osteoporosis, because it reduces postmenopausal bone resorption. Estrogen-replacement therapy is the answer to many problems caused by the harsh period of the menopause.

Oncogene. 2005 May 16;
Estrogen-induced G(1)/S transition of G(0)-arrested estrogen-dependent breast cancer cells is regulated by mitochondrial oxidant signaling.
Felty Q, Singh KP, Roy D.
1Department of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.

We previously reported that 17-beta-estradiol (E2)-induced mitochondrial reactive oxygen species (mtROS) act as signaling molecules. The purpose of this study was to investigate the effects of E2-induced mtROS on cell cycle progression. E2-induced cell growth was reduced by antioxidants N-acetyl-L-cysteine (NAC), catalase, and the glutathione peroxidase mimic ebselen. Flow cytometry showed that mitochondrial blockers of protein synthesis (chloramphenicol), transcription and replication (ethidium bromide), and function (rotenone, rhodamine 6G) blocked E2-induced G(1) to S transition. Reduction of E2-induced DNA synthesis in the presence of mitochondrial blockers occurred without influencing the level of ATP. Additionally, the mitochondrial blockers inhibited the E2-induced expression of early cell cycle genes such as cyclins D1, D3, E1, E2, and B2. NAC or rotenone reduced E2-induced cyclin D1 expression. Furthermore, E2-induced binding of AP-1 and CREB to the TRE and CRE response sequences, respectively, in the promoter of cyclin D1 was inhibited by NAC or rotenone. In addition, E2-induced expression of PCNA, PRC1, and bcl-2 were inhibited by mitochondrial blockers. These data indicate that E2-induced mtROS are involved in the regulation of early G(1)-phase progression. Since neither antioxidants nor mitochondrial blockers used in this study are reported to bind the estrogen receptor (ER), our findings suggest that E2-induced mtROS modulates G(1) to S transition and some of the early G(1) genes through a nongenomic, ER-independent signaling pathway. Thus, our results suggest (1) a new paradigm that estrogen-induced mitochondrial oxidants control the early stage of cell cycle progression and (2) provide the basis for the discovery of novel antioxidant-based drugs or antioxidant gene therapies for the prevention and treatment of estrogen-dependent breast cancer.Oncogene advance online publication, 16 May 2005; doi:10.1038/sj.onc.1208667.

Am J Cardiol. 2005 Jan 15;95(2):289-91.
Effect of hormone therapy on mortality rates among women with heart failure and coronary artery disease.
Bibbins-Domingo K, Lin F, Vittinghoff E, Barrett-Connor E, Hulley SB, Grady D, Shlipak MG.
Division of General Internal Medicine, San Francisco General Hospital, University of California-San Francisco, San Francisco, CA 94143, USA. bibbinsk@medicine.ucsf.edu

Randomized, controlled trial data from the Heart and Estrogen-progestin Replacement Study were used to evaluate the effect of estrogen plus progestin use on all-cause mortality in women with heart failure and coronary disease. Over the 4.1-year follow-up, estrogen plus progestin use had no effect on all-cause mortality (hazard ratio 1.0, 95% confidence interval 0.7 to 1.4, p = 0.8) in women with heart failure and coronary disease.

JAMA. 2005 Jan 19;293(3):330-9.
Effect of estrogen therapy on gallbladder disease.
Cirillo DJ, Wallace RB, Rodabough RJ, Greenland P, LaCroix AZ, Limacher MC, Larson JC.
Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, USA.

CONTEXT: Estrogen therapy is thought to promote gallstone formation and cholecystitis but most data derive from observational studies rather than randomized trials. OBJECTIVE: To determine the effect of estrogen therapy in healthy postmenopausal women on gallbladder disease outcomes. DESIGN, SETTING, AND PARTICIPANTS: Two randomized, double-blind, placebo-controlled trials conducted at 40 US clinical centers. The volunteer sample was 22,579 community-dwelling women aged 50 to 79 years without prior cholecystectomy. INTERVENTION: Women with hysterectomy were randomized to 0.625 mg/d of conjugated equine estrogens (CEE) or placebo (n = 8376). Women without hysterectomy were randomized to estrogen plus progestin (E + P), given as CEE plus 2.5 mg/d of medroxyprogesterone acetate (n = 14,203). MAIN OUTCOME MEASURES: Participants reported hospitalizations for gallbladder diseases and gallbladder-related procedures, with events ascertained through medical record review. Cox proportional hazards regression was used to assess hazard ratios (HRs) and 95% confidence intervals (CIs) using intention-to-treat and time-to-event methods. RESULTS: The CEE and the E + P groups were similar to their respective placebo groups at baseline. The mean follow-up times were 7.1 years and 5.6 years for the CEE and the E + P trials, respectively. The annual incidence rate for any gallbladder event was 78 events per 10,000 person-years for the CEE group (vs 47/10,000 person-years for placebo) and 55 per 10,000 person-years for E + P (vs 35/10,000 person-years for placebo). Both trials showed greater risk of any gallbladder disease or surgery with estrogen (CEE: HR, 1.67; 95% CI, 1.35-2.06; E + P: HR, 1.59; 95% CI, 1.28-1.97). Both trials indicated a higher risk for cholecystitis (CEE: HR, 1.80; 95% CI, 1.42-2.28; E + P: HR, 1.54; 95% CI 1.22-1.94); and for cholelithiasis (CEE: HR, 1.86; 95% CI, 1.48-2.35; E + P: HR, 1.68; 95% CI, 1.34-2.11) for estrogen users. Also, women undergoing estrogen therapy were more likely to receive cholecystectomy (CEE: HR, 1.93; 95% CI, 1.52-2.44; E + P: HR, 1.67; 95% CI, 1.32-2.11), but not other biliary tract surgery (CEE: HR, 1.18; 95% CI, 0.68-2.04; E + P: HR, 1.49; 95% CI, 0.78-2.84). CONCLUSIONS: These data suggest an increase in risk of biliary tract disease among postmenopausal women using estrogen therapy. The morbidity and cost associated with these outcomes may need to be considered in decisions regarding the use of estrogen therapy.

Exp Dermatol. 2005 Feb;14(2):156.
Perspectives of estrogen treatment in skin aging.
Schmidt JB.
Division of Special and Environmental Dermatology, University of Vienna Medical School, Wahringer Gurtel 18-20, A-1090 Vienna, Austria.

Clinical evidence of correlations between menopause and endogenous skin aging gave input to various studies investigating the relevance of estrogens for skin functions that are associated with skin aging and their possible therapeutic effects. Skin thickness and bone density are significantly decreased already six months after menopause and are increased after the same period of hormone replacement (HRT). Fibroblast and keratinocyte function is stimulated by estrogen application, and among other effects significant increases of collagen fibres have been demonstrated six months after the onset of HRT (1). Topical use of estrogen compounds was found to diminish skin aging symptoms. The effects of conjugated estrogens (0,625% Premarin) were studied in 60 postmenopausal women (2). In another study the effects of estradiol 0,01% and estriol 0,3% were compared (3). Both studies documented significant reductions of wrinkles without any systemic side effects of the treatments. Recently significant increases of epidermal thickness during estradiol have been described (4). For cosmetic purposes phytoestrogens seem a promising alternative to the medical treatment. Isoflavone containing cosmetical creams were shown to improve skin dryness and wrinkles (5). In various studies mainly beneficial effects of systemic HRT on skin aging parameters have been documented. Although skin aging is certainly no indication for systemic hormone supplementation the beneficial action of such treatment on aging symptoms of the skin are a positive side aspect of such treatment.

JAMA. 2005 Feb 23;293(8):935-48.
Effects of estrogen with and without progestin on urinary incontinence.
Hendrix SL, Cochrane BB, Nygaard IE, Handa VL, Barnabei VM, Iglesia C, Aragaki A, Naughton MJ, Wallace RB, McNeeley SG.
Department of Obstetrics and Gynecology, Wayne State University School of Medicine/Hutzel Women's Hospital, Detroit, Mich 48201, USA. shendrix@med.wayne.edu

CONTEXT: Menopausal hormone therapy has long been credited with many benefits beyond the indications of relieving hot flashes, night sweats, and vaginal dryness, and it is often prescribed to treat urinary incontinence (UI). OBJECTIVE: To assess the effects of menopausal hormone therapy on the incidence and severity of symptoms of stress, urge, and mixed UI in healthy postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS: Women's Health Initiative multicenter double-blind, placebo-controlled, randomized clinical trials of menopausal hormone therapy in 27,347 postmenopausal women aged 50 to 79 years enrolled between 1993 and 1998, for whom UI symptoms were known in 23,296 participants at baseline and 1 year. INTERVENTIONS: Women were randomized based on hysterectomy status to active treatment or placebo in either the estrogen plus progestin (E + P) or estrogen alone trials. The E + P hormones were 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate (CEE + MPA); estrogen alone consisted of 0.625 mg/d of conjugated equine estrogen (CEE). There were 8506 participants who received CEE + MPA (8102 who received placebo) and 5310 who received CEE alone (5429 who received placebo). MAIN OUTCOME MEASURES: Incident UI at 1 year among women without UI at baseline and severity of UI at 1 year among women who had UI at baseline. RESULTS: Menopausal hormone therapy increased the incidence of all types of UI at 1 year among women who were continent at baseline. The risk was highest for stress UI (CEE + MPA: relative risk [RR], 1.87 [95% confidence interval {CI}, 1.61-2.18]; CEE alone: RR, 2.15 [95% CI, 1.77-2.62]), followed by mixed UI (CEE + MPA: RR, 1.49 [95% CI, 1.10-2.01]; CEE alone: RR, 1.79 [95% CI, 1.26-2.53]). The combination of CEE + MPA had no significant effect on developing urge UI (RR, 1.15; 95% CI, 0.99-1.34), but CEE alone increased the risk (RR, 1.32; 95% CI, 1.10-1.58). Among women experiencing UI at baseline, frequency worsened in both trials (CEE + MPA: RR, 1.38 [95% CI, 1.28-1.49]; CEE alone: RR, 1.47 [95% CI, 1.35-1.61]). Amount of UI worsened at 1 year in both trials (CEE + MPA: RR, 1.20 [95% CI, 1.06-1.36]; CEE alone: RR, 1.59 [95% CI, 1.39-1.82]). Women receiving menopausal hormone therapy were more likely to report that UI limited their daily activities (CEE + MPA: RR, 1.18 [95% CI, 1.06-1.32]; CEE alone: RR, 1.29 [95% CI, 1.15-1.45]) and bothered or disturbed them (CEE + MPA: RR, 1.22 [95% CI, 1.13-1.32]; CEE alone: RR, 1.50 [95% CI, 1.37-1.65]) at 1 year. CONCLUSIONS: Conjugated equine estrogen alone and CEE + MPA increased the risk of UI among continent women and worsened the characteristics of UI among symptomatic women after 1 year. Conjugated equine estrogen with or without progestin should not be prescribed for the prevention or relief of UI.

Fertil Steril. 2004 Dec;82(6):1550-5.
Estrogen therapy increases plasma concentrations of nitric oxide metabolites in postmenopausal women but increases flow-mediated vasodilation only in younger women.
Lopez-Jaramillo P, Diaz LA, Pardo A, Parra G, Jaimes H, Chaudhuri G.
Vilano Group, Clinica Carlos Ardila Lulle, Universidad Autonoma de Bucaramanga and Fundacion Cardiovascular, Bucaramanga, Colombia. jplopezj@fcv.org

OBJECTIVE: To evaluate the effect of estrogen therapy (ET) on endothelial nitric oxide (NO) production and in flow-mediated vasodilation (FMV). DESIGN: Randomized, crossover, double-blind, placebo-controlled study. SETTING: Healthy postmenopausal women in an academic research environment. PATIENT(S): Forty postmenopausal women between 45 and 72 years of age. INTERVENTION(S): Women received ET or placebo during two periods of 12 weeks that were separated by 2 weeks of washout. MAIN OUTCOME MEASURE(S): Flow-mediated vasodilation, nitrite and nitrate, lipid profile, creatinine, and glucose were measured at weeks 12 and 24. Student's t or Wilcoxon tests were used for comparative analyses, and kappa test and limit analysis determined variability. RESULT(S): After placebo treatment, nitrate and nitrite mean concentration was 8.28 +/- 1.17 mmol/L; it increased to 62.6 +/- 12.82 mmol/L after ET. Percentage FMV was 18.8 +/- 2.58 after the placebo period and did not change after ET (20.1 +/- 1.92) in the whole sample, but in the subgroup (n = 15) of younger women (45-50 years of age), percentage FMV increased from 13.6 +/- 3.6 after the placebo period to 22.2 +/- 3.5 after ET. CONCLUSION(S): An increase in plasma concentrations of nitrite and nitrate after ET was observed in all the women studied, but the improvement in FMV was observed only in the younger ones. These age-related differences in FMV in response to ET must be further investigated.

Eur J Obstet Gynecol Reprod Biol. 2004 Nov 10;117(1):76-81.
Novel insight into the vaginal microflora in postmenopausal women under hormone replacement therapy as analyzed by PCR-denaturing gradient gel electrophoresis.
Devillard E, Burton JP, Hammond JA, Lam D, Reid G.
Canadian Research and Development Centre for Probiotics, The Lawson Health Research Institute, University of Western Ontario, 268 Grosvenor Street, London, Ont., Canada N6A 4V2.
Objectives: A study was conducted to use new molecular technologies to identify the vaginal bacterial species of postmenopausal women under oral estrogen therapy (Premarin-conjugated equine estrogen, CEE). Study design: Nineteen postmenopausal women under CEE treatment were recruited and their vaginal flora were analyzed during 3 months, using polymerase chain reaction in combination with denaturing gradient gel electrophoresis (DGGE) and sequencing of DNA fragments. Results: Sixty-eight percent of the women presented with a 'Normal' Nugent score at the first sampling time (d0). All the subjects had bacterial species detected in their vaginal flora. Lactobacillus species were detected in all samples. Moreover, 53% of the women had lactobacilli exclusively at d0. Two Lactobacillus species were dominant, and were recovered from the majority of samples (L. iners and L. crispatus). Forty-four percent of the samples also contained other bacterial species, which were potential urogenital pathogens. Candida albicans was detected in 26% of the subjects. The vaginal flora of the women under CEE treatment were different from that of postmenopausal women not receiving hormone therapy, but very similar to premenopausal women. Conclusions: The present study indicates that one benefit from hormone replacement therapy (HRT) is the restoration of a lactobacilli vaginal flora associated with a protective effect against urogenital infections.

JAMA. 2004 Oct 6;292(13):1581-7.
Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis.
Smith NL, Heckbert SR, Lemaitre RN, Reiner AP, Lumley T, Weiss NS, Larson EB, Rosendaal FR, Psaty BM.
Department of Epidemiology, University of Washington, Seattle, USA. nlsmith@u.washington.edu
CONTEXT: Clinical trial evidence indicates that estrogen therapy with or without progestins increases venous thrombotic risk. The findings from these trials, which used oral conjugated equine estrogens, may not be generalizable to other estrogen compounds. OBJECTIVE: To compare risk of venous thrombosis among esterified estrogen users, conjugated equine estrogen users, and nonusers. DESIGN, SETTING, AND PARTICIPANTS: This population-based, case-control study was conducted at a large health maintenance organization in Washington State. Cases were perimenopausal and postmenopausal women aged 30 to 89 years who sustained a first venous thrombosis between January 1995 and December 2001 and controls were matched on age, hypertension status, and calendar year. MAIN OUTCOME MEASURE: Risk of first venous thrombosis in relation to current use of esterified or conjugated equine estrogens, with or without concomitant progestin. Current use was defined as use at thrombotic event for cases and a comparable reference date for controls. RESULTS: Five hundred eighty-six incident venous thrombosis cases and 2268 controls were identified. Compared with women not currently using hormones, current users of esterified estrogen had no increase in venous thrombotic risk (odds ratio [OR], 0.92; 95% confidence interval [CI], 0.69-1.22). In contrast, women currently taking conjugated equine estrogen had an elevated risk (OR, 1.65; 95% CI, 1.24-2.19). When analyses were restricted to estrogen users, current users of conjugated equine estrogen had a higher risk than current users of esterified estrogen (OR, 1.78; 95% CI, 1.11-2.84). Among conjugated equine estrogen users, increasing daily dose was associated with increased risk (trend P value = .02). Among all estrogen users, concomitant progestin use was associated with increased risk compared with use of estrogen alone (OR, 1.60; 95% CI, 1.13-2.26). CONCLUSION: Our finding that conjugated equine estrogen but not esterified estrogen was associated with venous thrombotic risk needs to be replicated and may have implications for the choice of hormones in perimenopausal and postmenopausal women.

JAMA. 2004 Oct 6;292(13):1573-80.
Estrogen plus progestin and risk of venous thrombosis.
Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM, Stafford RS, Sidney S, Rosendaal FR; Women's Health Initiative Investigators.
Department of Medicine, University of Vermont, Burlington 05446, USA. mary.cushman@uvm.edu
CONTEXT: Postmenopausal hormone therapy increases the risk of venous thrombosis. It is not known whether other factors influencing thrombosis add to this risk. OBJECTIVE: To report final data on incidence of venous thrombosis in the Women's Health Initiative Estrogen Plus Progestin clinical trial and the association of hormone therapy with venous thrombosis in the setting of other thrombosis risk factors. DESIGN, SETTING, AND PARTICIPANTS: Double-blind randomized controlled trial of 16,608 postmenopausal women between the ages of 50 and 79 years, who were enrolled in 1993 through 1998 at 40 US clinical centers with 5.6 years of follow up; and a nested case-control study. Baseline gene variants related to thrombosis risk were measured in the first 147 women who developed thrombosis and in 513 controls. INTERVENTION: Random assignment to 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate, or placebo. MAIN OUTCOME MEASURES: Centrally validated deep vein thrombosis and pulmonary embolus. RESULTS: Venous thrombosis occurred in 167 women taking estrogen plus progestin (3.5 per 1000 person-years) and in 76 taking placebo (1.7 per 1000 person-years); hazard ratio (HR), 2.06 (95% confidence interval [CI], 1.57-2.70). Compared with women between the ages of 50 and 59 years who were taking placebo, the risk associated with hormone therapy was higher with age: HR of 4.28 (95% CI, 2.38-7.72) for women aged 60 to 69 years and 7.46 (95% CI, 4.32-14.38) for women aged 70 to 79 years. Compared with women who were of normal weight and taking placebo, the risk associated with taking estrogen plus progestin was increased among overweight and obese women: HR of 3.80 (95% CI, 2.08-6.94) and 5.61 (95% CI, 3.12-10.11), respectively. Factor V Leiden enhanced the hormone-associated risk of thrombosis with a 6.69-fold increased risk compared with women in the placebo group without the mutation (95% CI, 3.09-14.49). Other genetic variants (prothrombin 20210A, methylenetetrahydrofolate reductase C677T, factor XIII Val34Leu, PAI-1 4G/5G, and factor V HR2) did not modify the association of hormone therapy with venous thrombosis. CONCLUSIONS: Estrogen plus progestin was associated with doubling the risk of venous thrombosis. Estrogen plus progestin therapy increased the risks associated with age, overweight or obesity, and factor V Leiden.

Bone. 2004 Sep;35(3):682-8.
The oxidative metabolism of estrogen modulates response to ERT/HRT in postmenopausal women.
Armamento-Villareal RC, Napoli N, Klug T, Civitelli R.
Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA.
We have previously demonstrated that estrogen metabolism is one of the determinants of bone density after menopause. Increased hydroxylation to relatively nonestrogenic metabolites 2-hydroxyestrone (2OHE(1)) and 2-methoxyestrone (2MeOE(1)) was associated with low bone mineral density (BMD), while increased hydroxylation to the potent 16alpha-hydroxyestrone (16alphaOHE(1)) and weakly estrogenic estriol (E(3)) was associated with higher BMD. In this study, we tested the hypothesis that response to estrogen-hormone replacement therapy (ERT/HRT) is also related to individual differences in estrogen metabolism. Urinary estrogen metabolites were measured in 310 postmenopausal women using ESTRAMET enzyme immunoassay kit. Of these, 163 were on HRT with conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA, Premarin trade mark and Provera trade mark ) or ERT with conjugated equine estrogen alone (Premarin trade mark ), and 147 women not on ERT/HRT acted as comparison. Annual rates of BMD changes were calculated on a subset of 81 women on ERT/HRT who had more than one previous BMD measured by dual-energy X-ray absorptiometry (DEXA). Controlling for age, years since menopause (YSM), body mass index (BMI), waist to hip ratio, and smoking, we found that urinary estrogen metabolite levels were significantly higher in ERT/HRT-treated women compared to those not on ERT/HRT. Furthermore, women in the higher 2 tertiles of 2OHE(1) and 2OHE(1)/16√°OHE(1) ratio had positive increments in BMD compared to those in the lowest tertile who lost bone while on ERT/HRT. Thus, women with estrogen metabolism favoring the 2-hydroxylation pathway respond favorably to ERT/HRT.

Fertil Steril. 2004 Aug;82(2):384-90.
Effects of conjugated equine estrogen vs. raloxifene on serum insulin-like growth factor-i and insulin-like growth factor binding protein-3: a 2-year, double-blind, placebo-controlled study.
Duschek EJ, de Valk-de Roo GW, Gooren LJ, Netelenbos C.
Department of Endocrinology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands. e.duschek@vumc.nl
OBJECTIVE: To assess and compare the effect of conjugated estrogen and of the selective estrogen receptor modulator raloxifene on serum levels of insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) and on the IGF-I/IGFBP-3 ratio. DESIGN: A 2-year randomized, double-blind, placebo-controlled study. SETTING: Endocrinology outpatient department. PATIENT(S): Fifty-six postmenopausal, hysterectomized women. INTERVENTION(S): Women received raloxifene hydrochloride in doses of 60 mg/day (n = 15) or 150 mg/day (n = 13), conjugated equine estrogen (CEE) in doses of 0.625 mg/day (n = 15), or a placebo (n = 13) over the course of 2 years. MAIN OUTCOME MEASURE(S): At baseline and after 6, 12, and 24 months of treatment, serum levels of IGF-I, IGFBP-3, and insulin were measured, and an IGF-I/IFGBP-3 ratio was calculated. RESULT(S): Both raloxifene and CEE decreased serum IGF-I concentration. In contrast to CEE, which had no effect, both raloxifene doses of 60 and 150 mg/day significantly increased serum IGFBP-3 during the 2 years. Compared with placebo, the decrease in IGF-I/IGFBP-3 ratio was -32.5% (95% CI: -20.1; -44.8%) for CEE; -16.4% (95% CI: -3.6; -29.2%) for raloxifene at 150 mg/day; and -15.4% (95% CI: -1.0; -29.8%) for raloxifene at 60 mg/day. No effect of CEE or raloxifene was found on insulin concentration at any time point. CONCLUSION(S): Long-term use of both CEE and raloxifene decreases serum IGF-I and the IGF-I/IGFBP-3 ratio, but, unlike CEE, raloxifene produced a significant yet small increase in IGFBP-3.

J Pediatr Endocrinol Metab. 2004 Aug;17(8):1125-32.
Congenital adrenal hypoplasia and male pseudohermaphroditism due to DAX1 mutation, SF1 mutation or neither: a patient report.
AvRuskin TW, Krishnan N, Juan CS.
The Brookdale University Hospital and Medical Center, Department of Pediatrics, Division of Endocrinology and Metabolism and State University of New York, Health Sciences Center, Brooklyn, NY 11212-3198, USA. tavruski@brookdale.edu
A 15 year-old African American phenotypic female with congenital adrenal hypoplasia and intra-abdominal testes is described; she received cortisone acetate, 9alpha-Florinef, Premarin and Provera for maintenance therapy. Evaluation for DAX1, SF1 mutations using Southern blotting, PCR, PCR amplification, coding sequences, and splice site analyses have not detected any genetic abnormalities. While only 30% of the reported DAX1 mutation defects have been identified by a variety of genetic laboratory techniques, it remains probable that this unusual patient has either a DAX1 or SF1 mutation defect. A Wnt-4 defect was not evaluated.

J Clin Oncol. 2004 Jul 15;22(14):2842-8.
Post-treatment change in serum estrone predicts mammographic percent density changes in women who received combination estrogen and progestin in the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.
Ursin G, Palla SL, Reboussin BA, Slone S, Wasilauskas C, Pike MC, Greendale GA.
Department of Preventive Medicine, Norris Comprehensive Cancer Center, Room 4407, USC Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, CA 90089, USA. gursin@usc.edu
PURPOSE: Postmenopausal estrogen and progestin therapy (EPT) increases mammographic percent density and breast cancer risk substantially more than does estrogen therapy alone. We determined whether increases in serum estrone as a function of treatment predict increases in mammographic percent density. METHODS: We measured mammographic percent density and serum estrone levels in participants in the Postmenopausal Estrogen/Progestin Interventions Trial who were randomly assigned to receive conjugated equine estrogens (CEE) 0.625 mg/d; CEE and medroxyprogesterone acetate (MPA) 10 mg on days 1 to 12 per 28-day cycle; CEE and MPA 2.5 mg/d; or CEE and micronized progesterone (MP) 200 mg on days 1 to 12 per 28-day cycle. We used linear regression to determine whether serum estrone changes predicted mammographic percent density changes from baseline to 1 year. RESULTS: Mammographic percent density increased with increasing change in estrone level in the EPT groups, but not in the CEE group. Combined, the mammographic percent density in the three EPT groups demonstrated an absolute increase of 2.95% per 100 pg/mL increase in serum estrone level (P =.0003). The absolute increases were 4.09% (P =.0018) in the CEE + MPA continuous group, 2.79% (P =.0292) in the CEE + MPA cyclical group, and 1.40% (P =.36) in the CEE + MP group, but the differences among the EPT groups were not statistically significant. CONCLUSION: Greater increase in serum estrone level as a function of treatment is a significant predictor of increase in mammographic percent density in women randomly assigned to the combination of estrogen and progestin.

Acta Obstet Gynecol Scand. 2004 Jul;83(7):661-6.
Effect of conjugated equine estrogen in combination with two different progestogens on the risk factors of coronary heart disease in postmenopausal Chinese women in Taiwan: a randomized one-year study.
Chang TC, Lien YR, Chen M, Cheng SP, Chen RJ, Chow SN.
Department of Obstetrics and Gynecology, National Taiwan University Hospital, and College of Medicine, Taipei, Taiwan.
BACKGROUND: To compare the effect of hormone replacement therapy (HRT) using estrogen plus dydrogesterone or estrogen plus medroxyprogesterone acetate (MPA) on the risk factors for coronary heart disease (CHD) in postmenopausal women. METHODS: A randomized, prospective 1-year clinical trial was designed. All of the postmenopausal women (n = 279) received sequential conjugated equine estrogen (CEE) at a dose of 0.625 mg/day for 25 days (days 1-25) of each month. These women were also randomly assigned to receive either dydrogesterone 10 mg/day (E + D group, n = 140) or MPA 5 mg/day (E + P group, n = 139) for 14 days (days 12-25) of each month. Serum biochemical markers, lipoproteins, plasma prothrombin time (PT), partial prothrombin time (PPT) and antithrombin III-antigen (ATIII-Ag) were analyzed at baseline, and after 6 and 12 months of treatment. RESULTS: Liver function, renal function, PT and PPT did not change significantly during the 12-month trial. The E + D group had a more pronounced increase in high density lipoprotein cholesterol (HDL-C) than the E + P group (10.6% vs. 2.7%) after 12 months of treatment (p < 0.05). Both groups showed reduced concentrations of total cholesterol (T-CHO), low density lipoprotein cholesterol (LDL-C) and ATIII, whereas triglyceride (TG) was increased at the end of the trial (without intergroup difference). CONCLUSIONS: Our study demonstrated a favorable effect on lipoprotein profiles with both hormone replacement therapy regimens. Dydrogesterone appears to be superior to medroxyprogesterone acetate from the perspective of modification of coronary heart disease risk factors.

J Clin Endocrinol Metab. 2004 Jul;89(7):3462-8.
Breast and uterine effects of soy isoflavones and conjugated equine estrogens in postmenopausal female monkeys.
Wood CE, Register TC, Anthony MS, Kock ND, Cline JM.
Comparative Medicine Clinical Research Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1040, USA. chwood@wfubmc.edu
In this study we evaluated the long-term effects of soy isoflavones on intermediate markers of cancer risk in the normal postmenopausal monkey breast and uterus. Ovariectomized female cynomolgus monkeys were randomized to receive one of three diets for 36 months: 1) isoflavone-depleted soy protein isolate (SPI-) (n = 57); 2) soy protein isolate with the equivalent of 129 mg/d isoflavones (SPI+) (n = 60); or 3) isoflavone-depleted soy protein isolate with conjugated equine estrogens at a dose scaled to approximate 0.625 mg/d in women (n = 62). End points included breast and uterine proliferation markers, sex steroid receptor expression, and serum estrogens. Epithelial proliferation and progesterone receptor expression in the breast and uterus were significantly higher in the conjugated equine estrogen group, compared with SPI+ and SPI- groups, whereas no significant differences were detected between the SPI+ and SPI- groups. SPI+ treatment resulted in significantly lower serum concentrations of estrone (P < 0.01) and estradiol (P < 0.05) vs. SPI-. Within the SPI+ group, serum isoflavone concentrations were inversely correlated with serum estrone and mammary glandular area. These findings suggest that high dietary levels of soy isoflavones do not stimulate breast or uterine proliferation in postmenopausal monkeys and may contribute to an estrogen profile associated with reduced breast cancer risk.

Menopause. 2004 Jul-Aug;11(4):438-46.
The association between hormone therapy use and changes in strength and body composition in early postmenopausal women.
Maddalozzo GF, Cardinal BJ, Li F, Snow CM.
Bone Research Laboratory, Department of Exercise and Sport Science, Oregon State University, Corvallis, OR 97331-6802, USA. gianni.maddalozzo@oregonstate.edu
OBJECTIVE: To prospectively examine potential differences in upper- and lower-body muscle strength, lower-body power, lean muscle mass, total body fat, intra-abdominal fat, and energy expenditure (METS) variables in early postmenopausal women. Measurements were taken at baseline and 12 months. DESIGN: Prospective, 1-year non-randomized [self-selected hormone therapy (HT) and non-HT-replaced], longitudinal study with participation from 136 normally active, early [14.2 +/- 9.8 mo past menopause (51.1 +/- 3.0 y) mean age +/- SD] postmenopausal women. Total body fat mass, lean mass, and bone mass were assessed by dual-energy x-ray absorptiometry (Hologic), METS (6-mo activity recall questionnaire) upper- and lower-body peak force by isokinetic dynamometry (KinCom 500H, Chattex Corp.), and leg power by the Bassey Power Rig (Nottingham, UK). RESULTS: We observed no significant differences in central adipose tissue, total fat mass, lean muscle mass, strength, or lower limb power. However, estrogen did promote a maintenance affect in bone mineral density at the spine and total hip and an increase in greater trochanter bone mineral density (P < 0.01) in the estrogen-replaced group. CONCLUSION: Our findings suggest that HT does not play a role in either increasing or maintaining strength, lean muscle mass, lower limb power, or the attenuation of increases in total body or abdominal fat, at least in this group of postmenopausal women during the initial years of menopause

JAMA. 2004 Jun 23;291(24):2959-68.
Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study.
Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, Hsia J, Margolis KL, Hogan PE, Wallace R, Dailey M, Freeman R, Hays J; Women's Health Initiative Memory Study.
Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. mespelan@wfubmc.edu
CONTEXT: The Women's Health Initiative Memory Study (WHIMS) previously reported that estrogen plus progestin therapy does not protect cognition among women aged 65 years or older. The effect of estrogen-alone therapy, also evaluated in WHIMS, on cognition has not been established for this population. OBJECTIVES: To determine whether conjugated equine estrogen (CEE) alters global cognitive function in older women and to compare its effect with CEE plus medroxyprogesterone acetate (CEE plus MPA). DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled ancillary study of the Women's Health Initiative (WHI), WHIMS evaluated the effect of CEE on incidence of probable dementia among community-dwelling women aged 65 to 79 years with prior hysterectomy from 39 US academic centers that started in June 1995. Of 3200 eligible women free of probable dementia enrolled in the WHI, 2947 (92.1%) were enrolled in WHIMS. Analyses were conducted on the 2808 women (95.3%) with a baseline and at least 1 follow-up measure of global cognitive function before the trial's termination on February 29, 2004. INTERVENTIONS: Participants received 1 daily tablet containing either 0.625 mg of CEE (n = 1387) or matching placebo (n = 1421). MAIN OUTCOME MEASURE: Global cognitive function measured annually with the Modified Mini-Mental State Examination (3MSE). RESULTS: During a mean follow-up of 5.4 years, mean (SE) 3MSE scores were 0.26 (0.13) units lower than among women assigned to CEE compared with placebo (P =.04). For pooled hormone therapy (CEE combined with CEE plus MPA), the mean (SE) decrease was 0.21 (0.08; P =.006). Removing women with dementia, mild cognitive impairment, or stroke from the analyses lessened these differences. The adverse effect of hormone therapy was more pronounced among women with lower cognitive function at baseline (all P<.01). For women assigned to CEE compared with placebo, the relative risk of having a 10-unit decrease in 3MSE scores (>2 SDs) was estimated to be 1.47 (95% confidence interval, 1.04-2.07). CONCLUSION: For women aged 65 years or older, hormone therapy had an adverse effect on cognition, which was greater among women with lower cognitive function at initiation of treatment.

JAMA. 2004 Jun 23;291(24):2947-58.
Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study.
Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH; Women's Health Initiative Memory Study.
Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. sshumake@wfubmc.edu
CONTEXT: The Women's Health Initiative Memory Study (WHIMS) previously found increased risk for dementia and no effect on mild cognitive impairment (MCI) in women treated with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA). OBJECTIVE: To determine the effects of CEE alone and CEE plus MPA on incidence of probable dementia and MCI in older women. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled clinical trials of CEE (estrogen-alone trial) or CEE plus MPA (estrogen plus progestin trial) in community-dwelling women aged 65 to 79 years, conducted from June 1995 to July 8, 2002 (estrogen plus progestin; n = 4532), or to February 29, 2004 (estrogen-alone; n = 2947), in 39 of the 40 WHI clinical centers. INTERVENTIONS: In the estrogen-alone trial, 1 daily tablet containing either 0.625 mg/d of CEE vs matching placebo; in the estrogen plus progestin trial, 1 daily tablet containing CEE (0.625 mg/d) plus MPA (2.5 mg/d) vs matching placebos. MAIN OUTCOME MEASURES: Probable dementia and MCI. RESULTS: In the estrogen-alone trial, 47 participants were diagnosed with probable dementia, of whom 28 were assigned to CEE and 19 to placebo (hazard ratio [HR], 1.49; 95% confidence interval [CI], 0.83-2.66). Incidence rates for probable dementia in the estrogen-alone trial were statistically similar to those in the estrogen plus progestin trial (45 vs 22 per 10 000 person-years for CEE plus MPA vs placebo, respectively; P =.11). When data were pooled per the original WHIMS protocol, the overall HR for probable dementia was 1.76 (95% CI, 1.19-2.60; P =.005). After excluding participants with baseline Modified Mini-Mental State Examination scores at or below the screening cut point, the HR was 1.77 (95% CI, 0.74-4.23; P =.20) in the estrogen-alone trial and 2.19 (95% CI, 1.25-3.84; P =.006) in the pooled trials. In the estrogen-alone trial, 76 participants were diagnosed with MCI in the CEE group vs 58 in the placebo group (HR, 1.34; 95% CI, 0.95-1.89). In the combined trial data, the HR was similar (1.25; 95% CI, 0.97-1.60). In the estrogen-alone trial, 93 participants receiving CEE were diagnosed with either probable dementia or MCI vs 69 receiving placebo (HR, 1.38; 95% CI, 1.01-1.89; P =.04). CONCLUSIONS: Estrogen therapy alone did not reduce dementia or MCI incidence and increased the risk for both end points combined. Pooling data for estrogen alone and estrogen plus progestin resulted in increased risks for both end points. Use of hormone therapy to prevent dementia or cognitive decline in women 65 years of age or older is not recommended.

Maturitas. 2004 Jun 15;48(2):137-46.
Effects of continuous combined conjugated estrogen/medroxyprogesterone acetate and 17beta-estadiol/norethisterone acetate on lipids and lipoproteins.
Odmark IS, Backstrom T, Haeger M, Jonsson B, Bixo M.
Department of Clinical Science, Obstetrics and Gynecology, Umea University, S-901 85, Sweden.
OBJECTIVES: Various estrogen/progestogen combinations used in hormonal replacement therapy (HRT) have been reported to influence lipid and lipoprotein fractions differently. This motivated a comparative study where the two continuous combined regimens most commonly used in Sweden during the 1990s have been studied regarding effects on lipid profile. METHODS: In a 1-year prospective, double-blind study, 62 post-menopausal women were randomized to conjugated estrogen (CE), 0.625 mg, and medroxyprogesterone acetate (MPA), 5 mg, or 17beta-estradiol (E2), 2 mg, and norethisterone acetate (NETA), 1 mg. Serum concentrations of lipids and lipoproteins were measured at baseline and after 1 year of treatment. RESULTS: Both treatment groups significantly lowered the lipoprotein(a) (Lp(a)) levels. The CE/MPA group showed no significant changes in total cholesterol (TC), high-density (HDL) and low-density lipoprotein (LDL), but a significant increase of triglyceride (TG) levels. The E2/NETA group developed a significant lowering of total cholesterol, HDL, and LDL, but no significant changes of TG levels. The magnitude of change in serum concentrations of total cholesterol, HDL and TG differed significantly between the two treatment groups. CONCLUSIONS: Continuous combined treatment with CE/MPA and E2/NETA equally lowered Lp(a), an important risk factor for cardiovascular disease in women. Apart from this, the two treatments produced different effects on lipids and lipoproteins, findings that are more delicate to interpret.

Maturitas. 2004 Jun 15;48(2):107-13.
Effect of hormone replacement therapy and tibolone on serum leptin levels in postmenopausal women.
Lambrinoudaki IV, Christodoulakos GE, Panoulis CP, Rizos DA, Dendrinos SG, Liakakos T, Augoulea AD, Creatsas GC.
Second Department of Obstetrics and Gynecology, Aretaieion Hospital, University of Athens, 3 Neofytou Douka Street, GR-10674, Greece.
OBJECTIVE: To evaluate the effect of estrogen replacement therapy (ERT), continuous combined hormone replacement therapy (HRT) and tibolone on serum leptin levels in healthy postmenopausal women. METHODS: Eighty-four healthy postmenopausal women aged 43-63 years were studied prospectively. Hysterectomized women (n = 16) received conjugated equine estrogens (CEE) 0.625 mg. Women with an intact uterus were randomly allocated either to CEE+medroxyprogesterone acetate (CEE/MPA) 5 mg or tibolone 2.5 mg. Serum leptin levels were assessed at baseline and after 6 months of treatment. RESULTS: The three groups did not differ with respect to age, body mass index (BMI) or baseline serum leptin levels. Overweight women (BMI > 25 kg/m2) had higher baseline leptin levels (27.0 +/- 11.4 ng/ml) compared to their lean counterparts (BMI < or = 25 kg/m2; leptin: 16.5 +/- 8.1 ng/ml, P = 0.0001). Neither CEE nor CEE/MPA had any effect on serum leptin levels at the end of 6 months either in overweight or in lean women (overweight: CEE baseline 34.4 +/- 13.3 ng/ml, 6 months 36.9 +/- 15.8, P = 0.89, CEE/MPA baseline 22.4 +/- 9.8 ng/ml, 6 months 26.8 +/- 8.7 ng/ml, P = 0.1; lean: CEE baseline 12.6 +/- 4.4 ng/ml, 6 months 13.2 +/- 5.8 ng/ml, P = 0.36, CEE/MPA baseline 17.2 +/- 10.6 ng/ml, 6 months 18.8 +/- 8.8 ng/ml, P = 0.31). Similarly serum leptin remained unchanged at the end of the study in both lean and overweight women on tibolone (overweight: baseline 22.9 +/- 8.1 ng/ml, 6 months 18.5 +/- 12 ng/ml, P = 0.37; lean: baseline 13.2 +/- 5.6 ng/ml, 6 months 17.3 +/- 8.4 ng/ml). CONCLUSION: BMI is a strong determinant of serum leptin levels in healthy postmenopausal women. Neither ERT/HRT nor tibolone exert any effect on serum leptin after 6 months in lean or overweight postmenopausal women. Further studies are required to verify the exact role of estrogen and tibolone on leptin production and function in postmenopausal women.

Prescrire Int. 2004 Jun;13(71):106-9.
Post-menopausal hormone replacement therapy (cont'd): risk-benefit balance in the hot seat.
(1) The results of a randomised placebo-controlled double-blind trial in 16 000 women (the WHI trial), published in 2002, showed that post-menopausal hormone replacement therapy based on sulphoconjugated equine oestrogen and medroxyprogesterone led to an excess risk of serious adverse events (pulmonary embolism, coronary events, stroke, and invasive breast cancer). (2) Further analysis showed that invasive breast cancer diagnosed in women treated with the hormone combination had a similar histology and grade to cancers diagnosed in the placebo group, but that they were larger and more advanced. (3) The excess risk of stroke was mainly due to ischaemic events. In the group treated with the hormone combination, the only identifiable risk factor was lengthy use of hormone replacement therapy before enrollment in the trial. (4) No subgroup of women at risk of coronary events was found apart from women with elevated LDL-cholesterol at enrollment. (5) In the WHIMS subtrial in women aged 65 years or more, the risk of dementia was twice as high in women receiving hormone therapy as in those receiving placebo. (6) In the British ESPRIT placebo-controlled trial, oral estradiol valerate, at a dose of 2 mg/day, was ineffective as secondary prevention of myocardial infarction. (7) Follow-up of a very large British cohort (the Million Women Study) showed a significantly increased risk of breast cancer with all types of hormone replacement therapy, including oestrogen-progestin combinations (relative risk 2.00; 95% confidence interval 1.88-2.12), oestrogen monotherapy (RR 1.30; 95% CI 1.21-1.40) and tibolone (RR 1.45; 95% CI 1.25-1.68). There was no significant difference between oestradiol and equine oestrogen, between medroxyprogesterone acetate and progestins derived from nortestosterone, between oral, transdermal and implanted oestrogen preparations, or between sequential and continuous regimens. (8) A Swedish cohort study and an American case-control study also showed a higher risk of breast cancer linked to progestin use. (9) In a small French epidemiological case-control study, the risk of thromboembolism was higher among women taking oral rather than transdermal estradiol as part of their hormone replacement therapy. (10) In practice, the risk-benefit ratios of the hormone replacement therapies most commonly used in France are poorly characterised. It is therefore logical to use the drugs with which we have most experience (in clinical trials or during lengthy follow-up). The benefits and drawbacks should be regularly discussed with women using hormone replacement therapy, and they should be closely monitored for signs of breast cancer or cardiovascular disease.

Schweiz Rundsch Med Prax. 2004 May 19;93(21):904-14.
Postmenopausal hormone replacement therapy and cardiovascular risk: role of conjugated equine estrogens and medroxyprogesterone acetate
Ortmann J, Traupe T, Vetter W, Barton M.
Medizinische Poliklinik, Departement fur Innere Medizin, Universitatsspital, Zurich.
Atherosclerosis is a chronic systemic inflammatory disease of the vasculature that accounts for the majority of morbidity and mortality in women. The incidence of atherosclerosis is low in premenopausal women and increases after ovariectomy. Experimental studies demonstrate inhibitory effects of natural estrogens on the progression of atherosclerosis. In contrast, results from recent hormone replacement trials using conjugated equine estrogens and medroxyprogesterone acetate in postmenopausal women showed no effects or even an increase in cardiovascular morbidity and mortality such as thrombosis or stroke. Therefore, conjugated equine estrogens alone or in combination with medroxyprogesterone acetate should not be recommended for the prevention or treatment of cardiovascular disease. Optimizing the risk factor profile such as cessation of smoking, normalizing body weight and blood pressure, regular physical activity, and statin treatment of patients with coronary artery disease remain important treatment options.

Gynecol Endocrinol. 2004 May;18(5):244-57.
Effect of hormone replacement therapy, tibolone and raloxifene on serum lipids, apolipoprotein A1, apolipoprotein B and lipoprotein(a) in Greek postmenopausal women.
Christodoulakos GE, Lambrinoudaki IV, Panoulis CP, Papadias CA, Kouskouni EE, Creatsas GC.
2nd Department of Obstetrics and Gynecology, University of Athens, Aretaieion Hospital, Athens, Greece.
The aim of this study was to assess the effect of estrogen, two regimens of continuous combined hormone replacement therapy (HRT), tibolone and raloxffene on serum lipid, apolipoprotein A1 and B and lipoprotein(a) levels in Greek postmenopausal women. A total of 350 postmenopausal women were studied in a prospective open design. Women were assigned to one of the following regimens depending on the presence of risk factors for osteoporosis, dimacteric symptoms and an intact uterus: conjugated equine estrogen 0.625 mg (CEE, n = 34), continuous combined CEE 0.625 mg plus medroxyprogesterone acetate (MPA) 5 mg, (n = 80), continuous combined 17beta-estradiol 2 mg plus norethisterone acetate (NETA) 1 mg (n = 58), tibolone 2.5 mg (n = 83) and raloxifene HCl 60 mg (n = 50). Forty-five postmenopausal women with no indications for HRT served as controls. Total cholesterol (TC), low-density lipoprotein (LDL) cholestrol and high-density lipoprotein (HDL) cholesterol, triglyceride (TG), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and lipoprotein(a) (Lp(a)) levels were assessed in each subject at baseline, and at 6 and 12 months of therapy. All therapy regimens lowered TC levels compared to baseline (4.2-8.0% decrease). This effect was more prominent in the subgoup of women with high baseline TC levels (9.1-20.4% decrease). LDL cholesterol decreased significantly in CEE, CEE/MPA and raloxifene groups (-11.2%, -11.9% and -11.0%, respectively). Hypercholesterolemic women exhibited a steeper decrease in LDL cholesterol (10.6-27.8% in all therapy groups). TG levels increased significantly in the CEE and CEE/MPA groups (23.7% and 21.8%, respectively), while estradiol/NETA had no effect on TG levels. Tibolone decreased TG levels markedly, by 20.6%, while raloxifene had no TG-lowering effect. HDL cholesterol and ApoA1 were increased by CEE and CEE/MPA (HDL cholesterol, 7.4% and 11.8%, respectively; ApoA1, 17.8% and 7.9%, respectively) and decreased by tibolone (HDL cholesterol, -13.6%; and ApoA1, -9.9%). All therapy regimens except raloxifene lowered Lp(a) levels, with tibolone having the more pronounced effect (-13.2 to -29.0%). In conclusion, each therapy regimen had a diferent effect on lipid-lipoprotein levels, exerting favorable and unfavorable modifications. Hypercholesterolemic women seemed to benefit more from the cholesterol-lowering effect of estrogen replacement therapy/HRT. The choice for a particular regimen should be based on individual needs, indications and lipid-lipoprotein profile.

Int J Fertil Womens Med. 2004 May-Jun;49(3):120-2.
Mood modifications with raloxifene and continuous combined estrogen plus progestin hormone therapy.
Carranza-Lira S, MacGregor-Gooch AL, Sarachaga-Osterwalder M.
Gynecologic Endocrinology Service Luis Castelazo Ayala, Gynecology and Obstetrics Hospital, Mexico DF. scarranzal@mexis.com
OBJECTIVE: To assess the differences in effect between raloxifene and continuous combined estrogen plus progestin therapy on Hamilton Depression Rating Scale (HDRS) score. METHODS: Fifteen post-menopausal patients who had not received, and were not receiving, hormone therapy were studied. They were divided into two groups according to the therapy they received, as follows: group I, conjugated equine estrogens (CEE) 0.625 mg/day plus medroxyprogesterone 2.5 mg/day (n = 6), group II, raloxifene 60 mg/day (n = 9). The Hamilton Depression Rating Scale was used at baseline and after 6 months of treatment for mood assessment. Student's t test for independent samples was used for comparison among the groups; Student's t test for paired samples was used to assess differences between baseline and final Hamilton Depression Rating Scale scores. RESULTS: No differences were found in age or in anthropometric variables, in final Hamilton Depression Rating Scale score between the groups. In analyzing each group independently, no significant difference was found between baseline and final scores in Hamilton Depression Rating Scale in group I, while in group II a significant decrease was found. CONCLUSIONS: Raloxifene induces a greater decrease in Hamilton Depression Rating Scale, which indicates an amelioration of depressive mood during the climacteric.

JAMA. 2004 Jan 7;291(1):47-53.
National use of postmenopausal hormone therapy: annual trends and response to recent evidence.
Hersh AL, Stefanick ML, Stafford RS.
Stanford Prevention Research Center, Program on Prevention Outcomes and Practices, Stanford University School of Medicine, Stanford, Calif 94305, USA.
CONTEXT: Postmenopausal hormone therapy use increased dramatically during the past 2 decades because of a prevailing belief in its health benefits. Recent evidence from randomized trials published in July 2002 demonstrated adverse cardiovascular disease events and other risks with hormone therapy in the form of oral estrogen combined with progestin. OBJECTIVE: To describe patterns of hormone therapy use from 1995 until July 2003, including the impact of recent evidence. DESIGN, SETTING, AND POPULATION: Two databases were used to describe national trends in hormone therapy use from January 1995 to July 2003. The National Prescription Audit database provided data on the number of hormone therapy prescriptions filled by retail pharmacies and the National Disease and Therapeutic Index database provided data on patient visits to office-based physicians during which hormone therapy was prescribed. MAIN OUTCOME MEASURES: Annual number of hormone therapy prescriptions and characteristics of visits to physicians during which hormone therapy was prescribed. RESULTS: Annual hormone therapy prescriptions increased from 58 million in 1995 to 90 million in 1999, representing approximately 15 million women per year, then remained stable through June 2002. Adoption of new oral estrogen/progestin combinations, primarily Prempro, accounted for most of this growth. Obstetrician/gynecologists provided more than 70% of hormone therapy prescriptions, and more than one third of patients were older than 60 years. Following the publication of trial results in July 2002, hormone therapy prescriptions declined in successive months. Relative to January-June 2002, prescriptions from January-June 2003 declined by 66% for Prempro and 33% for Premarin. Small increases were observed in vaginal formulations and in new prescriptions for low-dose Premarin. If prescription rates observed through July 2003 remain stable, a decline to 57 million prescriptions for 2003, similar to the rate in 1995, is projected. CONCLUSIONS: Clinical practice responded rapidly to recent evidence of harms associated with hormone therapy. Since July 2002, many patients have discontinued hormone therapy or are tapering to lower doses.

JAMA. 2003 Oct 1;290(13):1729-38.
Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial.
Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ, LeBoff M, Lewis CE, McGowan J, Neuner J, Pettinger M, Stefanick ML, Wactawski-Wende J, Watts NB; Women's Health Initiative Investigators.
Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pa 15261, USA.
CONTEXT: In the Women's Health Initiative trial of estrogen-plus-progestin therapy, women assigned to active treatment had fewer fractures. OBJECTIVE: To test the hypothesis that the relative risk reduction of estrogen plus progestin on fractures differs according to risk factors for fractures. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial (September 1993-July 2002) in which 16 608 postmenopausal women aged 50 to 79 years with an intact uterus at baseline were recruited at 40 US clinical centers and followed up for an average of 5.6 years. INTERVENTION: Women were randomly assigned to receive conjugated equine estrogen, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). MAIN OUTCOME MEASURES: All confirmed osteoporotic fracture events that occurred from enrollment to discontinuation of the trial (July 7, 2002); bone mineral density (BMD), measured in a subset of women (n = 1024) at baseline and years 1 and 3; and a global index, developed to summarize the balance of risks and benefits to test whether the risk-benefit profile differed across tertiles of fracture risk. RESULTS: Seven hundred thirty-three women (8.6%) in the estrogen-plus-progestin group and 896 women (11.1%) in the placebo group experienced a fracture (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.69-0.83). The effect did not differ in women stratified by age, body mass index, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of hormone therapy, BMD, or summary fracture risk score. Total hip BMD increased 3.7% after 3 years of treatment with estrogen plus progestin compared with 0.14% in the placebo group (P<.001). The HR for the global index was similar across tertiles of the fracture risk scale (lowest fracture risk tertile, HR, 1.20; 95% CI, 0.93-1.58; middle tertile, HR, 1.23; 95% CI, 1.04-1.46; highest tertile, HR, 1.03; 95% CI, 0.88-1.24) (P for interaction =.54). CONCLUSIONS: This study demonstrates that estrogen plus progestin increases BMD and reduces the risk of fracture in healthy postmenopausal women. The decreased risk of fracture attributed to estrogen plus progestin appeared to be present in all subgroups of women examined. When considering the effects of hormone therapy on other important disease outcomes in a global model, there was no net benefit, even in women considered to be at high risk of fracture.


Menopause. 2003 Sep-Oct;10(5):420-6.
Better oral reading and short-term memory in midlife, postmenopausal women taking estrogen.
Shaywitz SE, Naftolin F, Zelterman D, Marchione KE, Holahan JM, Palter SF, Shaywitz BA.
Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06510-8064, USA.
OBJECTIVE: Considerable controversy surrounds the issue of whether estrogen influences cognitive function in postmenopausal women, and the results are far from consistent. For the most part, the cognitive processes studied have involved memory; to our knowledge, no previous studies have specifically examined the effects of estrogen on women's reading ability. DESIGN: To investigate reading and short-term memory in postmenopausal women treated with conjugated equine estrogens, we carried out a randomized, double-blind, placebo-controlled trial of 21 days in 60 midlife, postmenopausal women aged 32.8 to 64.9 years (mean 51.2 years, SD 5.0 years). Women were evaluated for oral reading measured by Gray Oral Reading Tests (third edition) and for verbal memory using immediate and delayed recall on the Logical Memory and Paired Associate Learning subtests of the Wechsler Memory Scale and by a Sentence Span task. RESULTS: The group receiving daily treatment with conjugated equine estrogens (Premarin, 1.25 mg; Wyeth-Ayerst Labs, Philadelphia, PA, USA) showed better oral reading and verbal memory performance than the placebo group. CONCLUSION: Estrogen may have positive effects on oral reading and verbal memory in midlife, postmenopausal women.

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