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Objective: This study aims to examine whether blood pressure reductions differ by estrogen use among overweight glucose-intolerant women., Methods: We conducted a secondary analysis of Diabetes Prevention Program postmenopausal participants who used oral estrogen with or without progestogen at baseline and 1-year follow-up (n = 324) versus those who did not use oral estrogen with or without progestogen at either time point (n = 382). Changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were examined by randomization arm (intensive lifestyle change [ILS], metformin 850 mg twice daily, or placebo). Associations between changes in blood pressure and changes in sex hormone-binding globulin, estradiol, testosterone, and dehydroepiandrosterone were also examined., Results: Estrogen users and nonusers had similar prevalences of baseline hypertension (33% vs 34%, P = 0.82) and use of blood pressure medications at baseline (P = 0.25) and on follow-up (P = 0.10). Estrogen users and nonusers randomized to ILS had similar decreases in SBP (-3.3 vs -4.7 mm Hg, P = 0.45) and DBP (-3.1 vs -4.7 mm Hg, P = 0.16). Among estrogen users, women randomized to ILS had significant declines in SBP (P = 0.016) and DBP (P = 0.009) versus placebo. Among nonusers, women randomized to ILS had significant declines in DBP (P = 0.001) versus placebo, but declines in SBP were not significant (P = 0.11). Metformin was not associated with blood pressure reductions versus placebo regardless of estrogen therapy. Blood pressure changes were not associated with changes in sex hormones regardless of estrogen therapy., Conclusions: Among overweight women with dysglycemia, the magnitude of blood pressure reductions after ILS is unrelated to postmenopausal estrogen use.

Objective: It is unclear how lipids change in response to lifestyle modification or metformin among postmenopausal glucose intolerant women using and not using hormone therapy (HT). We examined the one-year changes in lipids among postmenopausal, prediabetic women in the Diabetes Prevention Program (DPP), and whether changes were mediated by sex hormones., Materials/methods: We performed a secondary analysis of a randomized controlled trial of 342 women who used HT at baseline and year 1 and 382 women who did not use HT at either time point. Interventions included intensive lifestyle (ILS) with goals of weight reduction of at least 7% of initial weight and 150 minutes per week of moderate intensity exercise, or metformin or placebo administered 850 mg up to twice a day. Women were not randomized to HT. Main outcome measures were changes between baseline and study year 1 in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides., Results: Compared to placebo, both ILS and metformin significantly reduced LDL-C and raised HDL-C among HT users, changes partially explained by change in estradiol and testosterone but independent of changes in waist circumference and 1/fasting insulin. In contrast, DPP interventions had no effect on LDL-C and HDL-C among non-HT users. ILS significantly lowered triglycerides among non-users but did not significantly change triglycerides among HT users. Metformin did not significantly change triglycerides among non-users but increased triglycerides among HT users., Conclusions: The beneficial effects of ILS and metformin on lowering LDL-C and raising HDL-C differ depending upon concurrent HT use., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Among postmenopausal women who do not use estrogen therapy (ET), we have previously reported that intensive lifestyle modification (ILS) leads to increases in sex hormone-binding globulin (SHBG) and that such increases are associated with reductions in fasting plasma glucose (FPG) and 2-hour postchallenge glucose (2HG). Oral ET decreases FPG and increases 2HG while increasing both SHBG and estradiol (E2). It is unknown if ILS reduces glucose among ET users, if changes in SHBG and E2 might mediate any glucose decreases in ET users, and if these patterns differ from those in non-ET users., Methods: We conducted a secondary analysis of postmenopausal women in the Diabetes Prevention Program who used ET at baseline and 1-year follow-up (n = 324) and who did not use ET at either time point (n = 382). Participants were randomized to ILS, metformin, or placebo administered at 850 mg BID., Results: ET users were younger, more often white, and more likely to have had bilateral oophorectomy than non-ET users. Among ET users, ILS reduced FPG (P < 0.01) and 2HG (P < 0.01), and metformin reduced FPG (P < 0.01) but not 2HG (P = 0.56), compared with placebo. Associations between SHBG and total E2 with FPG and 2HG were not significant among women randomized to ILS or metformin. These patterns differed from those observed among women who did not use ET., Conclusions: We conclude that among glucose-intolerant ET users, interventions to reduce glucose are effective but possibly mediated through different pathways than among women who do not use ET.

Controlling for body size and composition, the authors examined the association between estrogen therapy and bone mineral density in older African-American and Caucasian women. In 1992-1998, 443 African-American and 989 Caucasian women aged 45-87 years were assessed for medication use, laboratory variables, behavioral characteristics, and bone mineral density. The mean age was 61.3 (95% confidence interval: 60.3, 62.3) years in African Americans and 71.0 (95% confidence interval: 70.4, 71.7) years in Caucasians (P < 0.001). All measures of body size and composition were significantly greater in the African-American women compared with Caucasian women (P < 0.001). As expected, African Americans had significantly higher bone mineral density at all 4 sites independent of age, weight, body composition, estrogen use, and lifestyle factors. Although Caucasians were significantly more likely to currently use estrogen (48.9% vs. 33.9%; P < 0.001), African Americans not using estrogen had significantly higher bone mineral density at all sites except the spine than Caucasians who were using estrogen. Regression models including age and lean mass explained the most variation in bone mineral density (R(2) range = 0.13-0.37). Results suggest that higher levels of bone mineral density in African-American women were not due to estrogen use.

Objective: This study examines the association of hormone use and lung cancer among women., Methods: This is a prospective study of 2,861 women aged 31 to 79 years from the Rancho Bernardo cohort. After enrollment in 1972 to 1974, women were followed up for 31 years for morbidity and mortality. Incident lung cancer was based on self-report or death certificates. Diagnosis was validated from the California Cancer Registry for cases that occurred after 1988. Cox proportional hazard models were used to estimate the adjusted association of hormone use and lung cancer., Results: During the 31-year follow-up, 87 women developed lung cancer. There was no association between hormone use and lung cancer (hazard ratio, 1.13; 95% CI, 0.73-1.73). Stratification by age 55 years (proxy for menopause status) showed divergent results. In women 55 years and older, lung cancer risk was 1.58 (95% CI, 0.95-2.53), whereas in women younger than 55 years, lung cancer risk was 0.44 (95% CI, 0.16-1.23). The confidence intervals for both groups contained the null value., Conclusions: Although not statistically significant, our results from a long follow-up suggest that postmenopausal women on hormone therapy may have an increased risk of lung cancer, whereas younger women do not.

There are more than 200 published scientific papers showing that estrogen has favorable effects on brain tissue and physiology in cell culture and animal models including non-human primates. The biological plausibility for a neuroprotective estrogen effect is overwhelming. However, most studies of endogenous estrogen and cognitive decline or dementia in women fail to show protection, and some suggest harm. Failure to find any consistent association might reflect the limitations of a single time of estrogen assay or poor assay sensitivity. More than half of the observational studies of hormone therapy suggest benefit. Nearly all long-term clinical trials fail to show benefit, and the longer trials tend to show harm. Failure to adequately adjust for self-selection of healthier and wealthier women and publication bias could account for some, or all, of the protective effect attributed to estrogen in observational studies. Overall, the evidence does not convincingly support the prescription of early or late postmenopausal estrogen therapy to preserve cognitive function or prevent dementia.

Unlabelled: Failure to take prescribed medication is common. The POSSIBLE US study is evaluating the impact of physician and patient characteristics on patient-reported compliance and persistence with osteoporosis medications. We report our study design and the baseline characteristics of 4,994 postmenopausal women recruited from primary care physician offices in 33 states., Introduction: The Prospective Observational Scientific Study Investigating Bone Loss Experience (POSSIBLE US) is a longitudinal cohort study of osteoporosis therapy in primary care., Methods: Between 2004 and 2007, 134 physicians (in 33 states) enrolled postmenopausal women initiating, changing, or continuing osteoporosis medications. After completing a baseline questionnaire, participants will provide data semi-annually for up to 3 years through 2008. Physicians provide patient data at baseline and routine follow-up visits. Participants from 23 sites also signed a release regarding administrative claims data for economic analyses and validation of self-reported data., Baseline Results: Four thousand nine hundred and ninety-four evaluable women were recruited from internal medicine (n = 1,784), family practice (n = 1,556), obstetrics/gynecology (n = 1,556), and from one rheumatology practice (n = 98). Mean participant age was 64.3 years (SD = 9.97); 89% were Caucasian; 59% had some college education. Sixty-three percent used a single osteoporosis agent, usually a bisphosphonate. For monotherapy patients, concordance between clinic- and patient-reported medication use was lowest for patients prescribed estrogen therapy (70%) or calcium/vitamin D (72%). Obstetrician/gynecologists enrolled younger women, who were more likely to use estrogen therapy than patients enrolled by other physicians. The 934 women (19%) prescribed only calcium/vitamin D were younger than women prescribed pharmacologic therapy., Conclusions: POSSIBLE US provides a unique foundation for evaluating longitudinal use of osteoporosis medications and related outcomes.

Largely on the basis of results from meta-analyses of observational studies, postmenopausal estrogen was widely prescribed to prevent coronary heart disease. However, epidemiologic studies, no matter how consistent and coherent, are not sufficient to recommend mass preventive therapy to healthy women. In fact, all three large clinical trials failed to confirm estrogen's expected cardiac protection. The most persistent explanatory hypothesis for the "trial failure" was the age of the participants, based on the thesis that estrogen in recently menopausal women could prevent the development of coronary artery plaque but, given to older women with vulnerable plaque, would have a null or even harmful effect. The timing hypothesis is plausible, but the prespecified subgroup analyses in both Women's Health Initiative trials showed no significant interaction with age or years since menopause. The best opportunity to test the timing hypothesis was lost when 1,000 Women's Health Initiative women younger than 60 years had coronary artery calcium scans to evaluate the effect of estrogen on plaque burden, but no women 60 years or over were similarly examined. Therefore, this ancillary study can examine the effect of estrogen treatment on coronary calcium in women younger than 60 years but will not be able to determine if the effect is different in older women. In the meantime, publicized statements in multiple venues have promoted the timing hypothesis as fact, confusing patients and physicians who do not realize that the hypothesis is stronger than the evidence.

Data Safety Monitoring Committees (DSMB) for large, long-term randomized trials of agents in common use face challenging problems especially when the emerging data indicate unanticipated effects. The DSMB for the Women's Health Initiative Clinical Trials, on observing early indication of a surprising adverse cardiovascular effect of post-menopausal hormones, spent several years deliberating what recommendations it should make. This paper describes the dilemmas faced by the DSMB and the considerations it made over the course of its existence. The paper concludes with some recommendations for other DSMBs.

Objective: To develop evidence and consensus-based recommendations for the use of hormone therapy (HT) in postmenopausal women., Design: Using evidence from clinical trials and other publications, a multidisciplinary group of women's health experts developed consensus-based recommendations for HT use in more than 300 clinical scenarios. These panelists utilized the RAND Appropriateness Method and a quantitative scale to rate the appropriateness of treatment options for women with various risk factors and clinical scenarios., Results: The panel judged it appropriate to prescribe all forms of HT to women with intolerable menopause symptoms and usual (age-expected) risks of cardiovascular disease (CVD), venous thromboembolism (VTE), or stroke. Use of HT was judged not appropriate for the clinical scenarios of bone preservation, cosmetic appearance, current memory loss, loss of libido, or CVD protection. For a woman still using HT after 5 or more years, it was considered appropriate to recommend the options of stopping or lowering the dose even if stopping was previously attempted. In treating intolerable symptoms in the presence of some elevated risk for diseases related to HT, route of administration may affect appropriateness but prior stroke or TIA# is a contraindication., Conclusions: Standard HT is appropriate for women with intolerable menopause symptoms in the absence of HT-related risk factors (eg, CVD, stroke, VTE, breast cancer). Panelists judged it appropriate to repeatedly present the option of stopping or reducing the dose. In most cases, presence of risk factors makes standard-dose oral HT not appropriate; however, some women may be candidates for a different dose or route of administration.

Objective: The objective of this study was to determine whether oral conjugated equine estrogen (CEE) alone or with one of the three progestin regimens causes changes in biomarkers predictive of adverse cardiovascular events: C-reactive protein (CRP), interleukin-6 (IL-6), intercellular adhesion molecule (ICAM) and matrix metalloproteinase-9 (MMP-9)., Methods and Results: The analysis included 271 postmenopausal women from the postmenopausal estrogen progestin intervention (PEPI) trial. Plasma levels of biomarkers were measured on frozen samples obtained at baseline, 1- and 3-year follow-up visits. Multivariable linear mixed effects models were used to estimate changes in CRP, IL-6, ICAM and MMP-9 levels from baseline to follow-up visits by treatment groups. Women assigned to CEE only or CEE plus a progestin had 121 and 150% 1-year increase in CRP levels, respectively. In contrast, these treatments caused no significant change in IL-6 levels. Women assigned to CEE with or without a progestin had a 6-8% decline in ICAM and a 26-33% decline in MMP-9., Conclusions: The linkage between CEE alone or with a progestin and increased cardiovascular events may be associated with a rise in CRP level, but not through the mechanisms of IL-6-mediated inflammation, endothelial dysfunction or increased MMP activity.

Objective: One putative benefit of hormone replacement therapy (HRT) is a reduced risk of diabetes or reduced fasting glucose level. We report here the association of HRT with proinsulin, insulin, and fasting and postchallenge glucose levels in older adults., Research Design and Methods: Current HRT use was validated and cross-sectionally compared with diabetes-related variables in 785 women without diabetes by history or glucose tolerance test., Results: Median age was 72 years (range 50-97); median value of fasting plasma glucose, postchallenge plasma glucose, and proinsulin was 5.08 mmol/l, 6.93 mmol/l, and 9.3 pmol/l, respectively. In age-adjusted comparisons, current HRT use was associated with significantly lower fasting plasma glucose and higher postchallenge plasma glucose compared with never/previous HRT use, as well as with lower LDL and higher HDL cholesterol and higher triglycerides. Fasting and postchallenge intact insulin did not differ by HRT group, but proinsulin was significantly lower in current HRT users than in previous and never HRT users. The significant association between proinsulin and HRT status persisted after adjustment for age, waist-to-hip ratio, pulse pressure, LDL-to-HDL cholesterol ratio, triglycerides, fasting and postchallenge glucose, and intact insulin., Conclusions: Reduced fasting and increased 2-h glucose replicate findings in a randomized clinical trial. The proinsulin effect has not been previously reported. Decreased fasting glucose and proinsulin levels in current HRT use suggest a potential antidiabetes effect of HRT. Increased postchallenge glucose in HRT, however, suggests insulin resistance and would be expected to increase the risk of heart disease.

Background: Previous studies have found polymorphisms of the HDL receptor, SR-BI, to be associated with plasma HDL-C in women, but not men, suggesting a modifying role of estrogen. We examined whether the association between SR-BI genotypes and HDL-C is modified by use of unopposed estrogen in community-dwelling postmenopausal Caucasian women., Methods: Common polymorphisms in Intron5 and Exon8 of the SR-BI gene were evaluated in 689 women from the Rancho Bernardo Study. Multiple linear regression analysis was carried out adjusting for confounders., Results: HDL-C levels did not differ significantly by genotype in the aggregate population. However, significant interaction was found between estrogen use and Exon8 (p=0.03), Intron5 (p=0.03) and Intron5/Exon8 diplotypes (p=0.01). SR-BI genotype was associated with HDL-C levels only among estrogen users (p=0.05) and explained 5.3% of the variance in HDL-C in this group. Consistent with prior studies, individuals heterozygous at both Intron5 and Exon8 loci had the lowest HDL-C levels. Among women with symptomatic CHD, the interaction between estrogen use and SR-BI genotype became even stronger., Conclusions: The effect that unopposed estrogen use has on HDL-C may depend on a woman's SR-BI genotype.

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.

Objective: To determine (1) whether past or current hormone therapy (HT) in postmenopausal women is associated with subclinical coronary artery plaque burden, (2) whether any association is independent of age, body size, blood pressure, lipids, fasting plasma glucose, cigarette smoking, leisure time physical activity, alcohol intake, use of lipid-lowering medications, and socioeconomic status, and (3) whether any association varies by duration of HT or by the use of combined versus unopposed HT., Design: An observational study, with HT validated and coronary heart disease risk factors determined between 1997 and 1999 in a research clinic, and coronary artery calcium score (CACS) evaluated by electron beam computed tomography in 2001 through 2002. Participants were 204 community-dwelling postmenopausal women from the Rancho Bernardo cohort aged 55 to 78 years with no history of heart disease., Results: The odds of severe CACS in current estrogen users (n = 127) was 0.40 (95% CI 0.19, 0.82), controlling for all covariates. Past users (n = 40) had intermediate odds (multiply adjusted OR = 0.66, 95% CI = 0.28, 1.58). In subgroup analyses, age-adjusted associations did not differ between the 68 women using unopposed estrogen versus the 59 using an estrogen-progestin regimen. Women who had used HT for at least 10 years (n = 86) had significantly less (P = 0.01) plaque burden than shorter term users (n = 41)., Conclusions: Both the strong association and the duration of use effect independent of lifestyle and social class suggest an antiatherogenic effect of postmenopausal estrogen. Only a clinical trial can completely exclude confounding by social class, lifestyle, and unmeasured covariates.

Clinical trials show that hormone therapy (HT) is an effective treatment for vasomotor symptoms and vaginal dryness. HT improves other symptoms including sleep and quality of life in women who have menopause symptoms. In the Women's Health Initiative controlled clinical trials, both estrogen therapy (ET) and estrogen plus progestin therapy (EPT) reduced fracture risk, neither reduced the risk of heart disease, and both increased the risk of stroke, deep vein thrombosis, and dementia. EPT, but not ET, increased breast cancer risk and reduced colon cancer risk. Differences between EPT and ET may reflect chance, baseline differences between the EPT and ET cohorts, or a progestin effect. Studies of younger women and lower HT doses with intermediate endpoints are beginning.

Objectives: We sought to explore the association between renal insufficiency and mortality among women with heart failure (HF) and to evaluate this risk by the presence of preserved or depressed systolic function., Background: Although HF is common in older women, little is known about their risk factors for mortality., Methods: This prospective cohort study retrospectively analyzed data from the Heart and Estrogen/progestin Replacement Study (HERS). Of the 2,763 women in HERS, 702 had HF. Renal function was categorized as creatinine clearance (CrCl) >60 ml/min, 40 to 60 ml/min, and <40 ml/min. We used proportional hazards models to evaluate the association between renal insufficiency and mortality., Results: Over a mean 5.8 years, 228 women with HF died (32%). Renal insufficiency was strongly associated with mortality, even after adjustment for co-morbid conditions, systolic function, and medications (adjusted hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.09 to 2.16 for CrCl 40 to 60 ml/min; adjusted HR 2.40, 95% CI 1.60 to 3.62 for CrCl <40 ml/min). Preserved or depressed systolic function did not modify the association between renal insufficiency and mortality risk, but the use of angiotensin-converting enzyme (ACE) inhibitors did modify this risk (ACE users: adjusted HR = 0.9, 95% CI 0.6 to 1.6; ACE nonusers: adjusted HR 2.1, 95% CI 1.3 to 3.2; p = 0.02 for interaction). Compared with other risk factors for mortality, renal insufficiency had the highest population attributable risk (27%)., Conclusions: Renal insufficiency was a major predictor of mortality among women with HF and preserved or depressed systolic function. This risk was attenuated by the use of ACE inhibitors.

Objective: Since the findings from the Women's Health Initiative became available in July 2002, millions of women have discontinued postmenopausal hormone therapy (HT). The objective of this study was to evaluate the association between HT cessation and hip fracture risk., Methods: Women who participated in the National Osteoporosis Risk Assessment and completed the 12-month follow-up survey were studied. All participants were aged at least 50 years, were postmenopausal, and had no previous diagnosis of osteoporosis. Baseline and 12-month follow-up questionnaires assessed use of HT and incident fractures. Of the 140,584 women in this study, 269 reported an incident hip fracture. A logistic regression model was used to assess association between HT use and incident hip fracture, controlling for potential confounders., Results: Consistent with the Women's Health Initiative, women in National Osteoporosis Risk Assessment who were currently on HT had a 40% lower incidence of hip fractures compared with those who never used HT. Women who stopped using HT more than 5 years earlier had similar hip fracture risk to never users, as expected. However, surprisingly, women who had discontinued HT within the previous 5 years had an increased hip fracture odds ratio of 1.65 (95% confidence interval 1.05, 2.59) relative to never users of HT., Conclusion: Postmenopausal women who have discontinued HT within the past 5 years have a risk for hip fracture that is at least as high as that in women who have never used HT., Level of Evidence: II-2

Objectives: Results from the Women's Health Initiative showed that postmenopausal hormone replacement therapy (HRT) prevents fractures but has an overall unfavorable risk:benefit ratio, leading to the recommendation that HRT be used only for women with troublesome menopause symptoms, and for as short a time as possible. This recommendation has important implications for the timing and duration of HRT and the prevention of osteoporosis. The large number of women participating in the National Osteoporosis Risk Assessment (NORA) program provided the opportunity to evaluate bone mineral density (BMD) and 1-year fracture risk in analyses stratified by duration and recency of HRT., Design: Participants were 170,852 postmenopausal women aged 50 to 104, without known osteoporosis, who were recruited from primary physicians offices across the US. BMD was measured at one of four peripheral sites, and the 1-year risk of osteoporotic fracture was assessed by questionnaire., Results: At baseline, current HRT users had the highest T-scores at every age. Among current hormone users, women who had used HRT longest had the highest BMD levels. Women who had stopped HRT more than 5 years previously, regardless of duration of use, had T-scores similar to never-users. Current but not past hormone use at baseline was associated with a 25% to 29% lower risk of osteoporotic fracture (P < 0.0001) in 1 year, compared with nonusers. These findings were independent of age, ethnicity, body mass index, lifestyle, years postmenopausal, and site of BMD measurement., Conclusions: We conclude that postmenopausal BMD and fracture are closely associated with current, but not prior, HRT use. Use of HRT for 5 years or less, as proposed for treatment of symptomatic women during menopause transition, is unlikely to preserve bone or significantly reduce fracture risk in later years.

Most studies of sex hormones and insulin resistance (IR) have focused on androgens; few have examined the association of endogenous estrogens and IR. We determined the cross-sectional association of endogenous levels of total and bioavailable testosterone and estradiol and SHBG with IR among 845 healthy, postmenopausal women aged 45-65 yr. Women were within 10 yr of menopause and not using hormone replacement therapy. Total adiposity was estimated by body mass index, visceral adiposity by waist to hip ratio (WHR), and IR by the homeostasis model assessment. We defined homeostasis model assessment-IR as the highest quartile (cutpoint, 2.1) of the distribution in this cohort. In logistic regression analyses, the odds for IR were significant and increased in a dose-response fashion across each quartile of total estradiol, bioavailable estradiol, and bioavailable testosterone (all P < 0.001 for linear trend). These associations remained significant after adjusting for WHR; adjusted odds ratios were 4.0, 6.1, and 2.7 for total estradiol, bioavailable estradiol, and bioavailable testosterone, respectively, comparing the highest to the lowest quartile (all P < 0.001). Adjusting for body mass index and WHR together eliminated the linear association of IR with total estradiol and bioavailable testosterone, but the association with bioavailable estradiol remained (adjusted odds ratio, 2.7; P < 0.001, comparing the highest to the lowest quartile). IR was not associated with total testosterone before or after adjusting for adiposity. Lower SHBG levels were associated with higher odds of IR, independent of adiposity. These results suggest that estrogen may be equally or more important than testosterone in the pathway to IR in healthy, young postmenopausal women, with differences not entirely explained by body size.

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.

Purpose: To determine if hormone therapy results in better cognitive function in older postmenopausal women., Subjects and Methods: The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized, placebo-controlled trial involving 2763 women with coronary disease. Women were assigned randomly to conjugated estrogen (0.625 mg) plus medroxyprogesterone acetate (2.5 mg) in one tablet daily or identical placebo; they were followed for a mean (+/- SD) of 4.2 +/- 0.4 years. Participants at 10 of the 20 HERS centers were invited to enroll in the cognitive function substudy. At the end of the trial, we measured cognitive function in 517 women in the hormone group and 546 in the placebo group using six standard tests: the modified Mini-Mental Status Examination, Verbal Fluency, Boston Naming, Word List Memory, Word List Recall, and Trails B. Cognitive function was not measured at baseline., Results: The mean age of participants at the time of cognitive function testing was 71 +/- 6 years. There were no differences in age-adjusted cognitive function test scores between the two treatment groups, except that women assigned to hormones scored worse on the Verbal Fluency test than women assigned to placebo (15.9 +/- 4.8 vs. 16.6 +/- 4.8, P = 0.02). Adjustment for other potential confounders and restriction of the analyses to women who had been adherent to study medication did not change the results., Conclusion: Among older postmenopausal women with coronary disease, 4 years of treatment with postmenopausal hormone therapy did not result in better cognitive function as measured on six standardized tests. Whether these results also apply to elderly women without coronary disease cannot be determined from this study.

Context: The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized trial of estrogen plus progestin therapy after menopause., Objective: To examine the effect of long-term postmenopausal hormone therapy on common noncardiovascular disease outcomes., Design and Setting: Randomized, blinded, placebo-controlled trial of 4.1 years' duration (HERS) and subsequent open-label observational follow-up for 2.7 years (HERS II), carried out between 1993 and 2000 in outpatient and community settings at 20 US clinical centers., Participants: A total of 2763 postmenopausal women with coronary disease and average age of 67 years at enrollment in HERS; 2321 women (93% of those surviving) consented to follow-up in HERS II., Intervention: Participants were randomly assigned to receive 0.625 mg/d of conjugated estrogens plus 2.5 mg of medroxyprogesterone acetate (n = 1380) or placebo (n = 1383) during HERS; open-label hormone therapy was prescribed at personal physicians' discretion during HERS II. The proportions with at least 80% adherence to hormones declined from 81% (year 1) to 45% (year 6) in the hormone group and increased from 0% (year 1) to 8% (year 6) in the placebo group., Main Outcome Measures: Thromboembolic events, biliary tract surgery, cancer, fracture, and total mortality., Results: Comparing women assigned to hormone therapy with those assigned to placebo, the unadjusted intention-to-treat relative hazard (RH) for venous thromboembolism declined from 2.66 (95% confidence interval [CI], 1.41-5.04) during HERS to 1.40 (95% CI, 0.64-3.05) during HERS II (P for time trend =.08); it was 2.08 overall for the 6.8 years (95% CI, 1.28-3.40), and 3 of the 73 women with thromboembolism died within 30 days due to pulmonary embolism. The overall RH for biliary tract surgery was 1.48 (95% CI, 1.12-1.95); for any cancer, 1.19 (95% CI, 0.95-1.50); and for any fracture, 1.04 (95% CI, 0.87-1.25). There were 261 deaths among those assigned to hormone therapy and 239 among those assigned to placebo (RH, 1.10; 95% CI, 0.92-1.31). Adjusted and as-treated analyses did not alter our conclusions., Conclusions: Treatment for 6.8 years with estrogen plus progestin in older women with coronary disease increased the rates of venous thromboembolism and biliary tract surgery. Trends in other disease outcomes were not favorable and should be assessed in larger trials and in broader populations.

Objective: We examined postmenopausal estrogen (PME) use and prevalence of clinical osteoarthritis (OA) at the hand, knee, and hip in 1001 community-dwelling postmenopausal women aged 43-97 years (mean age 72)., Methods: OA at the hip, hand, and knee was defined by validated and standardized criteria based on pain history plus a clinical examination performed by a specially trained nurse., Results: PME, validated by examination of pills and prescriptions, had been used for at least 1 year by 638 women (63.4%) for an average duration of 14.6 (+/-10.6) years. OA prevalence was 34.5% among women who had used PME for at least 1 year and 30.9% among women who did not use PME (age adjusted p = 0.02). Knee OA prevalence did not differ by PME use (p > 0.05). A significantly larger proportion of women who used PME for at least 1 year had hip and hand OA compared with women not using PME (4.1% vs. 1.1%, age-adjusted p = 0.002, and 15.8% vs. 13.5%, age-adjusted p = 0.02, respectively). In analyses adjusted for the potential confounding effects of age, body mass index (BMI), smoking, exercise, and type of menopause, women who used PME still were more likely to have hip OA (odds ratio [OR] = 5.03, confidence interval [CI] = 1.70-14.84, p = 0.003) and hand OA ([OR] = 1.57, CI = 1.05-2.33, p = 0.03). Among estrogen users, duration of PME use was longer for women with OA than for women without OA (16 vs. 11 median years, p = 0.01)., Conclusions: PME is associated with a higher prevalence of clinical OA.

Background: Accelerated bone loss after stopping hormone therapy (HRT) is postulated to explain the lack of hip-fracture protection conferred by former HRT use. The abbreviation HRT (traditionally standing for "hormone replacement therapy") is used herein because of its wide recognition in the field. However, the pharmacological doses of estrogens and progestins used are not truly "replacement" in nature., Objectives: To determine whether women lose bone mineral density (BMD) after stopping HRT; to assess whether their rate of loss is significantly greater than that of women not undergoing HRT; and to determine whether long-term HRT is associated with continued gains in BMD., Methods: A total of 495 women who were adherent to assigned treatment in the 3-year Postmenopausal Estrogen/Progestin Interventions randomized controlled trial (PEPI-RCT) and who had an additional BMD measurement during the PEPI Safety Follow-up Study were observed for an average of 3 years during and 4 years after the PEPI-RCT., Results: Women who stopped HRT after 1 year during the PEPI-RCT had annual rates of BMD change of -0.54% (hip) and -0.81% (spine) during the following 2 years. Those who underwent HRT for 3 years during the PEPI-RCT and then discontinued it had annual changes of -1.01% (hip) and -1.04% (spine). Rates of BMD loss among women who stopped HRT during or after the PEPI-RCT did not differ significantly from those of women who did not undergo HRT, who lost bone at a rate of approximately 1% yearly during the first year of the PEPI-RCT and about half that rate afterward. Women who continued HRT after the PEPI-RCT did not show additional BMD gains., Conclusions: Our results do not support the hypothesis that bone is lost at an unusually fast rate after discontinuation of HRT, nor do they suggest that longer-term HRT leads to additional BMD gain beyond that evident after 3 years.

The allelic variation of Apolipoprotein E (ApoE) influences serum lipid levels. Postmenopausal estrogen replacement therapy (ERT) has favorable effects on the serum lipid profile. We examined the effect of ApoE genotype on lipid response to ERT in 692 community-dwelling women aged 60 and older. ApoE genotypes were categorized into three groups: ApoE 2 (E2/E2+E2/E3, n=94), ApoE 3 (E3/E3, n=430), and ApoE 4 (E3/E4+E4/E4, n=142). Compared to 497 women not using ERT, 169 women currently using ERT were younger (P=0.01), had lower levels of total cholesterol (TC; P=0.10) and low-density lipoprotein (P<0.001), higher levels of high-density lipoprotein (HDL; P<0.001) and triglycerides (TG; P=0.009), and were more likely to have had a surgical menopause (P<0.001). No significant differences in body mass index, alcohol intake, physical activity, or cigarette smoking were found between current ERT users and nonusers (P>0.10). There was a significant interaction between ApoE 2 and ERT for HDL levels: women with ApoE 2 using ERT had the highest HDL levels, and women with ApoE 2 not using ERT had the lowest HDL levels (P=0.015). The unfavorable effect of ApoE 4 genotype on lipoproteins is not altered by HRT, but ApoE 2 genotype modulates the HDL-ERT association in older women.

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.

Despite the nearly universal finding from observational studies that postmenopausal estrogen therapy reduces the risk of CHD and the multiple plausible mechanisms by which estrogen might reduce the risk of CHD, hormone therapy had no benefit in the only large randomized clinical trial to date. Although it is possible that estrogen taken over the long term actually reduces CHD risk, it is not reasonable to begin the regimen used in HERS to prevent new or recurrent heart disease, given the observed excess early risk. Given the possible long term benefit, women who are already taking hormone replacement therapy may elect to remain on it. Women who are undecided should be asked to consider participation in clinical trials. The HERS has dramatically illustrated the need for them.

Studies of the effect of hormone replacement therapy (HRT) on the risk of stroke in postmenopausal women have yielded divergent results. Many of the studies had small numbers of estrogen-using women and relatively young women. All were confounded because women who use estrogen are healthier than the general population. Case-control studies, which included a larger number of cases, usually were limited to stroke survivors and had problems of recall bias regarding exposure. We describe the independent risk of fatal and nonfatal stroke in a socioeconomically homogeneous cohort of older, postmenopausal, community-dwelling women in Rancho Bernardo, California, who had a high rate of past or current HRT use. During 1984-1987, estrogen use and stroke risk factors were ascertained for 1031 women over age 60 without a history of stroke in the Rancho Bernardo cohort. Stroke deaths were monitored by obtaining 100% of death certificates, and nonfatal strokes were determined through questionnaires. At baseline, the average age was 73.1 years, 27% were current estrogen users, and 45% were past estrogen users. Over 8.8 follow-up years, 263 deaths occurred, and 37 of the death certificates listed stroke as an underlying or contributing cause of death. Only 7 of current HRT users had a stroke compared with 16 former users and 14 never users. The age-adjusted odds ratio (OR) was 0.92 (95% CI = 0.56-1.50) in HRT users versus never users. Results were not materially changed in multiply adjusted analyses. Similar analyses of nonfatal strokes and transient ischemic attacks (n = 20) showed an increased risk (OR = 3.02, 95% CI = 0.70-13.08). This study provides no evidence that HRT prevents stroke in older women, but the confidence intervals are wide, suggesting that more studies are needed.

Background: In longitudinal studies, greater mammographic density is associated with an increased risk for breast cancer., Objective: To assess differences between placebo, estrogen, and three estrogen-progestin regimens on change in mammographic density., Design: Subset analysis of a 3-year, multicenter, double-blind, randomized, placebo-controlled trial., Setting: Seven ambulatory study centers., Participants: 307 of the 875 women in the Postmenopausal Estrogen/Progestin Interventions Trial. Participants had a baseline mammogram and at least one follow-up mammogram available, adhered to treatment, had not taken estrogen for at least 5 years before baseline, and did not have breast implants., Intervention: Treatments were placebo, conjugated equine estrogens (CEE), CEE plus cyclic medroxyprogesterone acetate (MPA), CEE plus daily MPA, and CEE plus cyclic micronized progesterone (MP)., Measurements: Change in radiographic density (according to American College of Radiology Breast Imaging Reporting and Data System grades) on mammography., Results: Almost all increases in mammographic density occurred within the first year. At 12 months, the percentage of women with density grade increases was 0% (95% CI, 0.0% to 4.6%) in the placebo group, 3.5% (CI, 1.0% to 12.0%) in the CEE group, 23.5% (CI, 11.9% to 35.1%) in the CEE plus cyclic MPA group, 19.4% (CI, 9.9% to 28.9%) in the CEE plus daily MPA group, and 16.4% (CI, 6.6% to 26.2%) in the CEE plus cyclic MP group. At 12 months, the odds of an increase in mammographic density were 13.1 (95% CI, 2.4 to 73.3) with CEE plus cyclic MPA, 9.0 (CI, 1.6 to 50.1) with CEE plus daily MPA, and 7.2 (CI, 1.3 to 40.0) with CEE plus cyclic micronized progesterone compared with CEE alone., Conclusions: Further study of the magnitude and meaning of increased mammographic density due to use of estrogen and estrogen-progestins is warranted because mammographic density may be a marker for risk for breast cancer.

Objective: To assess pair-wise differences between placebo, estrogen, and each of three estrogen-progestin regimens on selected symptoms., Methods: This was a 3-year, multicenter, double-blind, placebo-controlled trial in 875 postmenopausal women aged 45-64 years at baseline. Participants were assigned randomly to one of five groups: 1) placebo, 2) daily conjugated equine estrogens, 3) conjugated equine estrogens plus cyclical medroxyprogesterone acetate, 4) conjugated equine estrogens plus daily medroxyprogesterone acetate, and 5) conjugated equine estrogens plus cyclical micronized progesterone. Symptoms were self-reported using a checklist at 1 and 3 years. Factor analysis reduced 52 symptoms to a set of six symptom groups., Results: In intention-to-treat analyses at 1 year, each active treatment demonstrated a marked, statistically significant, protective effect against vasomotor symptoms compared with placebo (odds ratios [ORs] 0.17-0.28); there was no additional benefit of estrogen-progestin over estrogen alone. Only progestin-containing regimens were significantly associated with higher levels of breast discomfort (OR 1.92-2.27). Compared with placebo, women randomized to conjugated equine estrogens reported no increase in perceived weight. Those randomized to medroxyprogesterone acetate reported less perceived weight gain (OR 0.61-0.69) than placebo. Anxiety, cognitive, and affective symptoms did not differ by treatment assignment. Analyses restricted to adherent women were not materially different than those using intention-to-treat, except that women adherent to medroxyprogesterone acetate and micronized progesterone regimens reported fewer musculoskeletal symptoms (OR 0.62-0.68)., Conclusion: These results confirm the usefulness of post-menopausal hormone therapy for hot flashes, show convincingly that estrogen plus progestin causes breast discomfort, and demonstrate little influence of postmenopausal hormones on anxiety, cognition, or affect.

Multiple health benefits have been postulated for the long-term use of hormone therapy in postmenopausal women, most notably for prevention of osteoporotic fractures and coronary heart disease, as well as several risks, including cancer of the breast and uterus and venous thromboembolism. Cardiovascular disease is the most common cause of death among postmenopausal women. If real, the reduction in risk of coronary heart disease by hormone use suggested by observational studies would likely outweigh the risks. The decision to initiate and maintain hormone therapy is complicated by uncertainties about estrogen's true benefits and risks. Raloxifene, a selective estrogen receptor modulator (SERM), appears to have many of the benefits of estrogen without the cancer risks. It is not known if SERMs can provide significant cardiovascular protection. This article reviews the relation of use of postmenopausal hormones and raloxifene to women's health and addresses the need for large randomized trials to quantify the effect of both postmenopausal estrogen and raloxifene on cardiovascular health.

Cardiovascular disease is the leading cause of death among older American women. Estrogen replacement therapy (ERT) appears to reduce the risk of heart disease. For nearly five decades, the Type A behavior pattern (TABP) has been implicated in the cardiac morbidity and mortality of both men and women, but no studies have examined the use of replacement estrogen or whether its association with heart disease risk factors is different in Type A versus Type B women. We examined the effects of ERT and TABP on heart disease risk factors in a large population-based sample. Subjects were 1070 postmenopausal women, aged 50-89 years, who had been participants in the Rancho Bernardo Study. At a clinic visit made during 1984-1987, TABP was assessed with the Bortner Rating Scale, and heart disease risk factors (total cholesterol, high-density and low-density lipoprotein (HDL and LDL), triglycerides, fasting and postchallenge insulin and glucose, and blood pressure) were measured. Based on a median split (median = 154.0) of scores on the Bortner Rating Scale, 52% of these women were classified as Type A. Type A women were significantly younger than Rating women (mean = 68.4 versus 71.0 years, respectively). After adjustment for age, significantly more Type A than Type B women were on ERT (35% versus 24.7%, p = 0.001). Analyses stratified by TABP indicated that within the Type A group, current users of ERT had higher levels of HDL cholesterol (p) = 0.001) and lower levels of LDL cholesterol (p < 0.01), fasting plasma glucose (p < 0.001), and fasting insulin (p < 0.01). Among Type B women, current users of ERT had higher levels of HDL cholesterol (p = 0.07) and triglycerides (p < 0.01), lower levels of LDL cholesterol (p < 0.01), and lower systolic blood pressure (p < 0.05) but no significant differences in either fasting or postchallenge levels of either plasma glucose or serum insulin (each p < 0.01). Results of this study suggest that ERT may be associated with significant differences in the heart disease risk factor profile in Type A versus Type B women, and these differences may favor Type A women.

Multiple observational studies suggest a marked reduction in risk of coronary heart disease (CHD) associated with postmenopausal estrogen use. A new meta-analysis presented here extends these results to estrogen plus progestin regimens. Although the findings from observational studies are strong and consistent, and there are several plausible mechanisms by which estrogen might reduce risk for CHD, most of the known biases would tend to exaggerate estrogen's benefit. Further, estrogen therapy clearly increases risk for endometrial hyperplasia and cancer, venous thromboembolic events and gallbladder disease, and long-term use probably also increases the risk of breast cancer. Therefore, until findings from randomized trials confirm and quantitate the benefit of estrogen therapy for prevention of CHD, we believe it should not be recommended to all postmenopausal women.

Objective: To assess the efficacy of unopposed estrogen, and three estrogen/progestin regimens on selected heart disease risk factors among adherent women and to contrast those results with efficacy among all women in the PEPI study., Design: A 3-year, multicenter, randomized, double-blinded, placebo-controlled clinical trial., Participants: A total of 847 healthy postmenopausal women aged 45 to 64 years of age with no known contraindication to hormone therapy, who attended their 36 month clinical visit., Intervention: Participants were randomized in equal numbers to one of the following treatments: (1) placebo; (2) conjugated equine estrogen (CEE) 0.625 mg daily; (3) CEE 0.625 daily plus medroxyprogesterone acetate (MPA) 10 mg, days 1-12; (4) CEE 0.625 daily plus MPA 2.5 mg daily; or (5) CEE 0.625 daily plus micronized progesterone (MP) 200 mg, days 1-12., Analysis: Analyses are based on adherent women, where adherence is defined as taking at least 80% of pills at each 6-month visit., Results: Adherence rates were high in all groups except women with a uterus assigned to unopposed CEE. The difference in HDL-C levels resulting from the CEE vs. CEE+MP was approximately three times larger than in the intent-to-treat analyses, reaching statistical significance (P < 0.05). In each active treatment, LDL-C decreased 10-15%. Triglycerides increased 15-20% in each opposed CEE arm and over 25% in the CEE only arm; this difference was not statistically significant. Fibrinogen increased by 7% among placebo adherers, but decreased or remained fairly stable among the active arm adherers. Systolic blood pressure increased 3-5% in all treatment arms. Women adherent to the CEE+MPA arms had twice the increase of 2 h glucose levels as women adherent to CEE only, or CEE+MP (8-9% vs. 3-4%). Two-hour insulin levels decreased 3-12% for all arms. The patterns of change for fibrinogen, SBP, 2 h glucose and insulin were similar to those from the intent-to-treat analyses., Conclusions: In analyses limited to adherent women, all active treatments, compared to placebo, continued to have similar and favorable effects on LDL-cholesterol and fibrinogen and no significant effects on blood pressure or insulin levels. Given the overall high adherence rates in PEPI, the results are similar to the intent-to-treat analyses, as expected. Only the trend of HDL-C to have a larger increase in the CEE only arm (in the intent-to-treat analyses) gained statistical significance in analyses restricted to adherers.

Objectives: This study examined the effect of postmenopausal estrogen replacement therapy on the incidence of non-insulin-dependent diabetes in women., Methods: Postmenopausal women aged 50 through 70 years (n=848) without diagnosed diabetes at baseline were followed for 10 to 15 years for incident diabestes., Results: Over the average 11.5 year follow-ip, there were 105 new cases of diabetes. The age-adjusted relative-risk for development of diabetes was nonsignificantly lower for women with continuous estrogen replacement therapy use than for never users. After adjustment for major covariates, a nonsignificant linear trend with increasing duration of estrogen replacement therapy was reversed., Conclusions: This study suggests that previous results showing a reduced risk of diabetes in women using estrogen may have been due to selection bias regarding who is prescribed estrogen, confounding factors, or differential diagnostic efforts.

Objective: To determine the effect of the timing of initiation and the duration of postmenopausal estrogen therapy on bone mineral density (BMD)., Design: Cross-sectional study., Setting: White, middle-class to upper middle-class community-dwelling women., Participants: A total of 740 women aged 60 to 98 years who participated in a study of osteoporosis., Measurements: Questionnaire, validated medication use, and height and weight. Bone mineral density at the ultradistal radius and midshaft radius using single-photon absorptiometry (SPA) and at the hip and lumbar spine using dual-energy x-ray absorptiometry (DEXA)., Results: Of the 740 women, 69% had used oral estrogen after menopause and 30% were current users. Five groups of estrogen use were identified: never users, past users who started at menopause, past users who started after age 60 years, current users who started after age 60 years, and current users who started at menopause. At all 4 bone sites, current users who started at menopause had the highest BMD levels, which were significantly higher than never users or past users who started at menopause (with 10 years' duration of use). These differences persisted after controlling for all major risk factors for osteoporosis. Among current users, there was no significant difference in BMD levels at any site between those who started estrogen at menopause (with 20 years of use) and those who started after age 60 years (with 9 years of use)., Conclusions: Estrogen initiated in the menopausal period and continued into late life is associated with the highest bone density. Nevertheless, estrogen begun after age 60 years and continued appears to offer nearly equal bone-conserving benefit.

Insulin-like growth factor-I (IGF-I) is associated with protein, carbohydrate, and bone metabolism. Results of previous studies examining the effect of exogenous estrogen on levels of IGF-I have been inconsistent. We examined the cross-sectional association between serum IGF-I levels and hormone replacement therapy (HRT) use in 672 postmenopausal women aged 50 yr and older. The mean age-adjusted IGF-I level was highest in the 415 women who reported never or past HRT use (126.8 micrograms/L), lowest in the 128 women who reported using estrogen alone (99.3 micrograms/L), and intermediate in the 115 women who reported using combination estrogen and progesterone (112.4 micrograms/L). A significant linear decline in mean age-adjusted IGF-I levels by duration of HRT use among all current users was seen. The decrease in serum IGF-I with current use of HRT is not consistent with the fact that both HRT and increased levels of IGF-I have been associated with improved glucose and bone metabolism and lipid profile. Further research is needed to evaluate the effect of the addition of a progestin to oral HRT on IGF-I-induced changes in GH levels.