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A critique of the Women’s Health Initiative Hormone Therapy Study

Klaiber EL, Vogel W, Rako S. Fertil Steril. 2005 Dec;83(6);1589-601.

Objective: This review critiques the Women’s Health Initiative (WHI) study, focusing on aspects of the study design contributing to the adverse events resulting in the studies discontinuation.

Conclusions:  Two aspects of the design contributed to the adverse events; [1] the decision to administer continuous combined conjugated equine estrogen (CEE)/medroxyprogesterone acetate (MPA) or E alone as a standard regimen to a population with little previous hormonal treatment, ranging in age from 50-79 years, who, because of their age, were predisposed to coronary and cerebral atherosclerosis. [2] Selection of an untested regimen of continuous combined CEE + MPA, which we hypothesize, negated the protective effect of E on the cardiovascular and cerebrovascular systems. Multiple observational studies that proceeded the WHI study concluded that the use of E alone and E + cyclic (not daily) progestin combination treatments initiated in early in menopause have beneficial effects. The therapeutic regimens resulted in prevention of atherosclerosis and reduction in coronary artery disease mortality. It is our conclusion that the WHI hormonal replacement study had major design flaws that led to adverse conclusions about the positive effects of hormone therapy. An alternative hormonal regimen is proposed that, on the basis of data supporting its beneficial cardiovascular effects, when initiated appropriately in a population of younger, more recently menopausal women, has promised to yield a more favorable risk/benefit outcome.

Effect of transdermal estradiol and oral conjugated estrogen on C-reactive protein, a marker for inflammation in healthy women

Circulation 2002 Sep3; 106(10):1224-8

Conclusion: In contrast to oral conjugated equine estrogen, Transdermal E2 does not elevate CRP levels up to 12 months of treatment.

Women beginning hormone therapy near menopause have significantly reduced risk of coronary heart disease

The Role of Time since Menopause and Age at Hormone Initiation

J Hormone Therapy and Coronary Heart Disease: Women’s Health (Larchmt) 2006 Jan/Feb;15(1)

Results: Women beginning hormone therapy (HT) near menopause had significantly reduced risk of coronary heart disease (CHD). Among women who initiated therapy at least 10 years after menopause no significant relation was found between HT and CHD. Among women who began taking hormones at older ages, we also found no relation between current use of estrogen alone and CHD although there was a suggestion of possible reduced risk for combined HT.

Conclusion: These data support the possibility that timing of HT initiation in relation to menopause onset or to age might influence coronary risk.

The effectiveness of Hormone Replacement therapy (HRT) in early (<67years) and late (>67years) post-menopausal women on bone status.

Clin Endocrinol (Oxf). 1996 Jan;44(1):79-84

Conclusions: Transdermal oestrogen is effective at preventing bone loss in the spine at all post-menopausal ages and is capable of doing this in low dosage.  Prevention of bone loss at the femoral neck is less certain.


Estrogen has protective effects on the cardiovascular system

Mendelsohn Tufts University School of Medicine, Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111, USA.

Am J Cardiol. 2002; 89(12A):12E-17E; discussion 17E-18E (ISSN: 0002-9149)

Estrogen has direct and indirect effects on the cardiovascular system that are mediated by the estrogen receptors ER-alpha and ER-beta. The direct effects of estrogen occur through rapid nongenomic and longer-term genomic pathways. The rapid effects of estrogen are mediated by ERs and result in the activation of endothelial nitric oxide synthase, leading to arterial vasodilation. Longer-term effects involve changes in gene and protein expression, modulating the response to injury and atherosclerosis. Estrogen also indirectly influences serum lipoprotein and triglyceride profiles, and the expression of coagulant and fibrinolytic proteins. Advanced atherosclerosis and certain progestins, however, may attenuate some of the protective effects of estrogen

Oestriol reduces recurrent urinary tract infections in postmenopausal women.

Kirkengen AL; Andersen P; Gjersøe E; Johannessen GR; Johnsen N; Bodd E
Department of Medicine, Red Cross Clinic, Oslo, Norway.

Scand J Prim Health Care. 1992; 10(2):139-42 (ISSN: 0281-3432)

A block randomized, double-blind, group-comparative, placebo-controlled study was conducted to assess the effect of oestriol on recurrent urinary tract infections in postmenopausal women. 40 women, median age 78 years (66-91), 20 in each group, were treated with oestriol three mg p.o. per day or corresponding placebo for four weeks, followed by one mg per day for eight weeks. The main response parameter was the number of urinary tract infections per week in the two treatment periods. Both oestriol and placebo reduced the number of infections per week significantly in both periods, compared with the pretreatment period. There was no difference between oestriol and placebo treatment in the first period. In the second period, however, oestriol treatment was significantly more effective than placebo (p = 0.05). Correspondingly, there was a significant difference between the two groups in the vaginal pH at the end of the study (p less than 0.05). We conclude that oestriol reduces recurrent urinary tract infections in postmenopausal women.

Estriol prevents post-menopausal bone loss and improves menopausal symptoms

Effect of Estriol on bone mineral density and bone metabolism in post-menopausal women

J Obstet Gynaecol Res. 1996 Jun;22(3):259-265

Minaguchi H, Uemura T, et al.

Objectives: To assess the effect of Estriol on the bone mineral density (BMD) and bone metabolism in postmenopausal women.

Methods: 75 naturally post-menopausal women with a BMD of more than 10% below the peak bone density were treated for 50 weeks with 2mg/day estriol (E3) cyclically and 0.8g/day of calcium lactate continuously. BMDs at L2-L4 were measured by dual energy X-ray absoeptiometry (DXA).

Results: The BMD increased 1.79% after 50 weeks, accompanied with decrease of biochemical markers of bone turnover. With regard to climacteric symptoms, Kupperman’s menopausal index improved (P < 0.01 vs pretreatment) after 5 weeks of treatment. As to the incidence of adverse events, genital bleeding was observed in only 8.0% of the subjects. Endometrial histology and cytology showed neither abnormalities nor hyperplasia during and after treatment.

Conclusions: Estriol prevented postmenopausal bone loss and improved climacteric symptoms effectively with low incidence of genital bleeding.

Estrogen may help slow the progression of Alzheimer’s Disease

17beta Estradiol reduces plasma Abeta40 for HRT-naïve post-menopausal women with Alzheimer’s Disease

Am J Geriatr Psychiatry. 2003 Mar-Apr;11(2):239-44

Baker LD, Sabamurti K, Craft S, Cherrier M, Raskind MA, Stanczyk FZ, Plymate SR, Asthana S.

Objectives: One mechanism to support the potentially beneficial effects of estrogen in the brain for postmenopausal women potentially involves the hormone’s ability to favorably alter the processing of amyloid-precursor protein (APP), believed to play an important role in the pathobiology of Alzheimer’s disease (AD). The authors evaluated the effects of estrogen administration on plasma concentration of one by-product of APP processing, Abeta40, for post-menopausal women with AD.

Conclusions: the results provide preliminary clinical evidence to support the effect of estradiol on A-beta processing for AD women who are HRT-naive. This finding suggests that the hormone may serve as a Abeta-lowering agent for HRT-naive AD women, which may in turn have ultimate ramifications for the progression of AD pathology.

Combined HRT with estradiol and progesterone is beneficial for quality of life, prevention of bone loss and cardiovascular profile without the activation of inflammatory markers and without increase in the relative risk of breast cancer

Combined Hormone Replacement therapy and risk of breast cancer in a cohort of 3175 women

De Lingnieres B, de Vathaire, Climacteric 2002;5:332-340

The largest-to-date randomized trial (women’s Health Initiative) comparing the effects of hormone replacement therapy (HRT) and a placebo concluded that the continuous use of an oral combination of conjugated equine estrogens (CEE) and medroxy-progesterone acetate (MPA) increases the risk of breast cancer. This conclusion may not apply to women taking other estrogen and progestin formulations as suggested by discrepancies in the findings of in vitro studies, epidemiological surveys and, mostly, in vivo studies of human breast epithelial cell proliferation showing opposite effects of HRT combining CEE plus MPA or estradiol plus progesterone. To evaluate the risk of breast cancer associated with the use of the latter combination, commonly prescribed in France, a cohort including 3175 postmenopausal women was followed for a mean of 8.9 years (28 367 women- years).  In total 1739 (55%) of these women were users of one type of estrogen replacement with systemic effect during at least 12 months, any time after menopause, and were classified as HRT users.  Among them 83% were receiving exclusively estradiol gel and a progestin other than MPA.  Some 105 cases of breast cancer occurred during the follow-up period, corresponding to a mean of 37 new cases per 10,000 women/ year. Using multivariate analysis adjusted for a calendar period of treatment, date of birth and age at menopause, we were unable to detect an increase in the relative risk (RR) of breast cancer (RR 0.98, 95% CI 0.97-1.05) in the users of HRT.  These results do not justify early interruption of such a type of HRT, which is beneficial for quality of life, prevention of bone loss and cardiovascular risk profile, without the activation of coagulation and inflammatory protein synthesis measured in users of oral estrogens.

HRT with transdermal estradiol alone or with cyclical progesterone improves type 2 diabetes, lowers total cholesterol and LDL cholesterol

The objective of this open, longitudinal controlled study was to assess the effect of transdermal estradiol alone or combined with cyclical dydrogesterone on the markers of cardiovascular disease (CVD) risk in postmenopausal women with type 2 diabetes. The control group consisted of postmenopausal diabetic women who declined menopausal hormone replacement therapy (HRT). 28 postmenopausal (19 on HRT and 9 controls) with type 2 diabetes were followed up for 12 months. From the active treatment group 14 women with a uterus in situ had 80microgram/24hr transdermal estradiol and oral dydrogesterone 10mg daily for the first 12 days of the calendar month whereas 5 women with previous hysterectomy had 80microg/24hr transdermal estradiol (Fematrix 80) alone. CVD risk markers were measured before and at regular intervals after starting HRT. The main outcome measures were weight, systolic and diastolic blood pressure, fasting plasma glucose, glycated hemoglobin (HbA1C) glucose/insulin ration, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density (LDL) cholesterol, triglycerides, lipoprotein (a), high sensitivity C reactive protein (hs-CRP), fibrinogen, and endothelin-1. Transdermal estradiol with or without dydrogesterone in women with type 2 diabetes did not adversely affect any of the measured markers of cardiovascular disease. There was a significant decrease in HbA1C, total cholesterol, and LDL cholesterol at 6 months in women receiving HRT. Some of the cardiovascular disease risk markers may improve in postmenopausal women with type 2 diabetes with transdermal estradiol. This effect may have important clinical implications and it deserves further investigation in appropriately designed trials.

Results From the Women's Health Initiative randomized controlled trial: Risks and benefits of estrogen plus progestin in healthy postmenopausal women

JAMA. 2002; 288(3):321-33 (ISSN: 0098-7484)

Division of Women's Health Initiative, National Heart, Lung, and Blood Institute, 6705 Rockledge Dr, One Rockledge Ctr, Suite 300, Bethesda, MD 20817, USA.rossouw@nih.gov

CONTEXT: Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain.

OBJECTIVE: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States.

DESIGN: Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998.

INTERVENTIONS: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).

MAIN OUTCOMES MEASURES: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.

RESULTS: On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years.

CONCLUSIONS: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.



The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.  Estrogen or estrogen/progestin regimen effects on heart disease risk factors in postmenopausal women

JAMA. 1995; 273(3):199-208 (ISSN: 0098-7484)

OBJECTIVE--To assess pairwise differences between placebo, unopposed estrogen, and each of three estrogen/progestin regimens on selected heart disease risk factors in healthy postmenopausal women.

DESIGN--A 3-year, multicenter, randomized, double-blind, placebo-controlled trial.

PARTICIPANTS--A total of 875 healthy postmenopausal women aged 45 to 64 years who had no known contraindication to hormone therapy.

INTERVENTION--Participants were randomly assigned in equal numbers to the following groups: (1) placebo; (2) conjugated equine estrogen (CEE), 0.625 mg/d; (3) CEE, 0.625 mg/d plus cyclic medroxyprogesterone acetate (MPA), 10 mg/d for 12 d/mo; (4) CEE, 0.625 mg/d plus consecutive MPA, 2.5 mg/d; or (5) CEE, 0.625 mg/d plus cyclic micronized progesterone (MP), 200 mg/d for 12 d/mo.

PRIMARY ENDPOINTS--Four endpoints were chosen to represent four biological systems related to the risk of cardiovascular disease: (1) high-density lipoprotein cholesterol (HDL-C), (2) systolic blood pressure, (3) serum insulin, and (4) fibrinogen.

ANALYSIS--Analyses presented are by intention to treat. P values for primary endpoints are adjusted for multiple comparisons; 95% confidence intervals around estimated effects were calculated without this adjustment.

RESULTS--Mean changes in HDL-C segregated treatment regimens into three statistically distinct groups: (1) placebo (decrease of 0.03 mmol/L [1.2 mg/dL]); (2) MPA regimens (increases of 0.03 to 0.04 mmol/L [1.2 to 1.6 mg/dL]); and (3) CEE with cyclic MP (increase of 0.11 mmol/L [4.1 mg/dL]) and CEE alone (increase of 0.14 mmol/L [5.6 mg/dL]). Active treatments decreased mean low-density lipoprotein cholesterol (0.37 to 0.46 mmol/L [14.5 to 17.7 mg/dL]) and increased mean triglyceride (0.13 to 0.15 mmol/L [11.4 to 13.7 mg/dL]) compared with placebo. Placebo was associated with a significantly greater increase in mean fibrinogen than any active treatment (0.10 g/L compared with -0.02 to 0.06 g/L); differences among active treatments were not significant. Systolic blood pressure increased and postchallenge insulin levels decreased during the trial, but neither varied significantly by treatment assignment. Compared with other active treatments, unopposed estrogen was associated with a significantly increased risk of adenomatous or atypical hyperplasia (34% vs 1%) and of hysterectomy (6% vs 1%). No other adverse effect differed by treatment assignment or hysterectomy status.

CONCLUSIONS--Estrogen alone or in combination with a progestin improves lipoproteins and lowers fibrinogen levels without detectable effects on postchallenge insulin or blood pressure. Unopposed estrogen is the optimal regimen for elevation of HDL-C, but the high rate of endometrial hyperplasia restricts use to women without a uterus. In women with a uterus, CEE with cyclic MP has the most favorable effect on HDL-C and no excess risk of endometrial hyperplasia.

Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women.

Thromb Haemost. 2001; 85(4):619-25 (ISSN: 0340-6245)

Vehkavaara S; Silveira A; Hakala-Ala-Pietilä T; Virkamäki A; Hovatta O; Hamsten A; Taskinen MR; Yki-Järvinen H
Department of Medicine, University of Helsinki, Finland.

We compared the effects of oral estradiol (2 mg), transdermal estradiol (50 microg), and placebo on measures of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in 27 postmenopausal women at baseline and after 2 and 12 weeks of treatment. Oral and transdermal estradiol induced similar increases in serum free estradiol concentrations. Oral therapy increased the plasma concentrations of factor VII antigen (FVIIag) and activated factor VII (FVIIa), and the plasma concentration of the prothrombin activation marker prothrombin fragment 1+2 (F1+2). Oral but not transdermal estradiol therapy significantly lowered plasma plasminogen activator inhibitor-1 (PAI-1) antigen and tissue-type plasminogen activator (tPA) antigen concentrations and PAI-1 activity, and increased D-dimer concentrations, suggesting increased fibrinolysis. The concentration of soluble E-selectin decreased and serum C-reactive protein (CRP) increased significantly in the oral but not in the transdermal or placebo groups. In the oral but not in the transdermal or placebo estradiol groups low-density-lipoprotein (LDL) cholesterol, apolipoprotein B and lipoprotein (a) concentrations decreased while high-density-lipoprotein (HDL) cholesterol, apolipoprotein AI and apolipoprotein All concentrations increased significantly. LDL particle size remained unchanged. In summary, oral estradiol increased markers of fibrinolytic activity, decreased serum soluble E-selectin levels and induced potentially antiatherogenic changes in lipids and lipoproteins. In contrast to these beneficial effects, oral estradiol changed markers of coagulation towards hypercoagulability, and increased serum CRP concentrations. Transdermal estradiol or placebo had no effects on any of these parameters. These data demonstrate that oral estradiol does not have uniformly beneficial effects on cardiovascular risk markers and that the oral route of estradiol administration rather than the circulating free estradiol concentration is critical for any changes to be observed.