Effect Of Menopausal Hormone Therapy Research Articles

Genetic modifiers of the effect of menopausal hormone therapy on breast cancer risk – A meta-analysis of four genome-wide association studies

Hormone therapy (HT) is associated with an elevated risk of breast cancer (BC) in postmenopausal women. Only limited studies have examined whether BC risk after HT exposure varies by individual susceptibility. To identify loci that modify HT related BC risk, four genome-wide case-only studies were analysed separately and combined in a meta-analysis. We included data from the genome-wide association studies HEBCS (Finland), MARIE (Germany), NHS (USA) and SASBAC (Sweden) which yielded 344, 742, 1,090 and 773 female, postmenopausal BC cases, respectively. Recruitment was hospital-based for HEBCS and population-based for MARIE, SASBAC and NHS. The available SNPs (genotyped using the Illumina 370k array in MARIE and 550 k in HEBCS, NHS and SASBAC) were used to impute additional SNPs (software: MACH) which resulted in up to 2,800,000 SNPs in total per study. The case-only approach is more powerful to detect gene-environment interactions than the case-control approach if the assumption of gene-environment independence is valid. We performed case-only logistic regression analysis for each study separately (outcome: current versus never/past HT use) using the software ProbABEL that takes into account the uncertainty introduced by imputation, i.e. the probabilities of each genotype per SNP and individual are used rather than the most likely genotype. A log-additive mode of inheritance is employed. The meta-analyses will be conducted assuming fixed effects (software: Plink). Our study has 80% power to detect an interaction effect of 1.25 assuming genetic and environmental main effects of 1.15, a moderate risk allele frequency of 0.10 and a prevalence of the environmental exposure of 0.50, Currently, analyses are ongoing and results will be presented at the conference. The most significant results will be replicated in independent case-control studies from the Breast Cancer Association Consortium (BCAC). We will thus rule out false positives due to possible gene-HT dependencies.

Potential Approaches to Enhance the Effects of Estrogen on Senescent Blood Vessels and Postmenopausal Cardiovascular Disease

Cardiovascular disease (CVD) is more common in postmenopausal than premenopausal women, suggesting vascular protective effects of estrogen. Vascular estrogen receptors ERalpha, ERbeta and a transmembrane estrogen-binding protein GPR30 have been described. Also, experimental studies have demonstrated vasodilator effects of estrogen on the endothelium, vascular smooth muscle and extracellular matrix. However, randomized clinical trials have not supported vascular benefits of menopausal hormone therapy (MHT), possibly due to the subjects' advanced age and age-related changes in estrogen synthesis and metabolic pathways, the vascular ERs number, distribution and integrity, and the post-ER vascular signaling pathways. Current MHT includes natural estrogens such as conjugated equine estrogen, as well as synthetic and semi-synthetic estrogens. New estrogenic formulations and hormone combinations have been developed. Phytoestrogens is being promoted as an alternative MHT. Specific ER modulators (SERMs), and selective agonists for ERalpha such as PPT, ERbeta such as DPN, and GPR30 such as G1 are being evaluated. In order to enhance the vascular effectiveness of MHT, its type, dose, route of administration and timing may need to be customized depending on the subject's age and pre-existing CVD. Also, the potential interaction of estrogen with progesterone and testosterone on vascular function may need to be considered in order to maximize the vascular benefits of MHT on senescent blood vessels and postmenopausal CVD.

Vascular Sex Hormone Receptors and their Specific Modulators in the Management of Postmenopausal Cardiovascular Disease

Cardiovascular disease (CVD) is more common in men and postmenopausal women than premenopausal women, suggesting vascular benefits of female sex hormones. Studies on the vasculature have identified estrogen receptors ERα, ERβ and a novel estrogen binding membrane protein GPR30, that mediate genomic and/or non-genomic effects. Estrogen promotes endothelium-dependent relaxation by inducing the production/activity of nitric oxide, prostacyclin, and hyperpolarizing factor, and inhibits the mechanisms of vascular smooth muscle contraction including [Ca(2+)](i), protein kinase C, Rho kinase and mitogen-activated protein kinase. Additional effects of estrogen on the cytoskeleton, matrix metalloproteinases and inflammatory factors contribute to vascular remodeling. However, the experimental evidence did not translate into vascular benefits of menopausal hormone therapy (MHT), and the HERS, HERS-II and WHI clinical trials demonstrated adverse cardiovascular events. The discrepancy has been partly related to delayed MHT and potential changes in the vascular ER amount, integrity, affinity, and downstream signaling pathways due to the subjects' age and preexisting CVD. The adverse vascular effects of MHT also highlighted the need of specific modulators of vascular sex hormone receptors. The effectiveness of MHT can be improved by delineating the differences in phramcokinetics and pharmacodynamics of natural, synthetic, and conjugated equine estrogens. Estriol, "hormone bioidenticals" and phytoestrogens are potential estradiol substitutes. The benefits of low dose MHT, and transdermal or vaginal estrogens over oral preparations are being evaluated. Specific ER modulators (SERMs) and ER agonists are being developed to maximize the effects on vascular ERs. Also, the effects of estrogen are being examined in the context of the whole body hormonal environment and the levels of progesterone and androgens. Thus, the experimental vascular benefits of estrogen can be translated to the outcome of MHT in postmenopausal CVD, as more specific modulators of sex hormone receptors become available and are used at the right dose, route of administration and timing, depending on the subject's age and preexisting cardiovascular condition.

Genetic polymorphisms in phase I and phase II enzymes and breast cancer risk associated with menopausal hormone therapy in postmenopausal women

Recent findings indicate a greater risk of postmenopausal breast cancer with estrogen-progestagen therapy than estrogen monotherapy, and more so for current than past use. Few studies have examined individual genetic susceptibility to the effects of menopausal hormone therapy. We used two population-based case-control studies with 3,155 postmenopausal breast cancer patients and 5,496 controls to evaluate modification of breast cancer risk associated with duration of hormone use by genes involved in hormone metabolism and detoxification. Twenty-eight polymorphisms in eight genes of phase I (CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP3A4, CYP3A5, CYP3A7) and nine genes of phase II enzymes (COMT, GSTM1, GSTM3, GSTP1, GSTT1, SULT1A1, UGT1A1, UGT1A6, UGT2B7) were genotyped. The risk associated with duration of use of combined estrogen-progestagen therapy was significantly modified by genetic polymorphisms located in CYP1B1, GSTP1, and GSTT1. In homozygote carriers of the CYP1B1_142_G and the CYP1B1_355 _T variant alleles, adjusted odds ratios (OR) per year of use were 1.06 (95% confidence interval (CI) = 1.02-1.09) and 1.06 (95% CI = 1.03-1.09), respectively, compared with 1.02 (95% CI = 1.01-1.03) in non-carriers of either polymorphism (p(interaction) = 0.01). Carriers of the functional GSTT1 allele and the GSTP1_341_T allele were at significantly higher risks associated with hormone use compared with non-carriers (p(interaction) = 0.0001 and 0.02). CYP1A1_2452_C>A significantly reduced the risk associated with duration of use of estrogen monotherapy (p(interaction) = 0.01). The finding regarding GSTT1 was still statistically significant after corrections for multiple comparisons. Postmenopausal breast cancer risk associated with hormone therapy may be modified by genetically determined variations in phase I and II enzymes involved in steroid hormone metabolism.

ACOG Committee Opinion No. 420: Hormone Therapy and Heart Disease

The effect of menopausal hormone therapy on coronary heart disease has been the subject of much concern. The Heart and Estrogen/Progestin Replacement Study (HERS) and Women's Health Initiative studies found an increased risk of cardiovascular events with conjugated equine estrogen and medroxyprogesterone acetate use. However, recent evidence suggests that women in early menopause who are in good cardiovascular health are at low risk of adverse cardiovascular outcomes and as such should be considered candidates for the use of conjugated equine estrogen or conjugated equine estrogen and medroxyprogesterone acetate for relief of menopausal vasomotor symptoms. Hormone therapy use should be limited to the treatment of menopausal symptoms at the lowest effective dosage over the shortest duration possible, and continued use should be reevaluated on a periodic basis.

Modulators of Vascular Sex Hormone Receptors and their Effects in Estrogen-Deficiency States Associated with Menopause

Cardiovascular disease (CVD) is more prevalent in postmenopausal than premenopausal women, suggesting vascular protective effects of estrogen. Also, experimental studies have demonstrated beneficial effects of estrogen in improving vascular function and reducing vascular injury. However, clinical trials including HERS I, HERS II, WHI and WISDOM have demonstrated minimal beneficial vascular effects of menopausal hormone therapy (MHT) in postmenopausal women with CVD. The discrepancies between the experimental findings and clinical data may be related to the vascular estrogen receptors (ER), the type, route of administration, or dosage of MHT, and subject's age. Vascular ERs mediate both genomic and non-genomic effects of estrogen on the endothelium, vascular smooth muscle (VSM), and extracellular matrix (ECM). Postmenopausal changes in vascular ER structure, polymorphisms, amount, subcellular location, affinity or signaling could modify their responsiveness to estrogen and thereby the outcome of MHT. Recent investigations and patents have been centered on developing new ER modulators and alternatives for the traditional natural and synthetic forms of MHT which carry the risk of invasive breast cancer and venous thromoboembolism. Phytoestrogens may have similar effects as traditional MHT and have not demonstrated harmful side effects. Specific estrogen receptor modulators (SERMs) such as raloxifene and tamoxifen have also been tested. ER agonists that selectively target ERalpha, ERbeta and perhaps GPR30 may modify specific vascular signaling pathways. Also, the dose, route of administration, and timing of MHT are integral to optimizing the beneficial effects and minimizing the side effects of MHT. Progesterone, testosterone and modulators of their specific receptors may also affect the overall vascular effects of MHT in estrogen-deficiency states associated with menopause.

Risk of different histological types of postmenopausal breast cancer by type and regimen of menopausal hormone therapy

In a large population-based case-control study in Germany, including 3,464 breast cancer cases aged 50-74 at diagnosis and 6,657 population based and frequency matched controls, we investigated the effects of menopausal hormone therapy (HT) by type, regimen, timing and progestagenic constituent on postmenopausal breast cancer risk overall and according to histological type. Data were collected by face-to-face interviews. Logistic and polytomous logistic regression analysis were used to estimate odds ratios (OR) and 95%-confidence intervals (95% CI). Risk of invasive breast cancer was significantly elevated in current users (OR, 1.73, 95% CI, 1.55-1.94) and heterogeneous by histological type (p < 0.01), being more than 2-fold higher for lobular and tubular than for ductal cancer. Risks for current users varied significantly by type and regimen of HT, with ORs per year of use of 1.05 (95% CI, 1.04-1.06) for continuous combined estrogen-progestagen, 1.03 (95% CI, 1.02-1.04) for cyclical EP and 1.01 (95% CI, 1.00-1.03) for estrogen-only therapy. No statistically significant increase in risk was observed after 5 years of cessation of HT use for any histological type. Analyses of progestagenic content by regimen revealed a significantly higher risk for continuously administered norethisterone- or levonorgestrel-derived progestagens than for continuously administered progesterone-derived progestagens (OR, 2.27, 95% CI, 1.98-2.62 vs. 1.47, 95% CI, 1.12-1.93, respectively, p = 0.003), which may be explained by dose rather than type of progestagen. These data suggest that the risks associated with menopausal HT differ by type and regimen of HT and histological type of breast cancer and may vary by progestagenic component, depending on the effective dose.

Lifestyle factors: Are they related to vasomotor symptoms and do they modify the effectiveness or side effects of hormone therapy?

This article reviews and summarizes published literature in order to address the following questions: (1) Are lifestyle factors (alcohol use, cigarette exposure, physical activity) and body mass index (BMI) related to the occurrence of vasomotor symptoms in perimenopausal and postmenopausal women?; and (2) Do lifestyle factors or BMI modify the effectiveness or side effects of menopausal hormone therapy (HT)? Information was culled from a nonstructured review of English-language literature. Moderate alcohol consumption (<1 drink per day for women) does not have a measurable effect on occurrence of vasomotor symptoms; whether greater amounts of alcohol intake would promote vasomotor symptoms cannot be addressed by available literature. Most published studies report that active cigarette smoking is positively associated with vasomotor symptoms. However, a large study found that passive (but not active) smoking (i.e., secondhand smoke exposure) was related to vasomotor symptoms. Studies to date do not support a relation between physical activity and vasomotor symptoms. However, rates of vasomotor symptom reporting were low in these studies, potentially limiting the ability to detect an effect of physical activity. Greater BMI is a risk factor for more vasomotor symptom reporting. The scarcity of data that directly address whether lifestyle factors or BMI modify the effects of HT precludes a substantive response to this question at present. Available literature suggests that smoking and higher body weight are risk factors for vasomotor symptoms; women with vasomotor symptoms who smoke may benefit from smoking cessation, and women who are heavier than ideal body weight may benefit from weight reduction. Whether certain behaviors or BMI raise or lower the risks or benefits of HT remains largely unknown and should be the focus of future research. This article reviews and summarizes published literature in order to address the following questions: (1) Are lifestyle factors (alcohol use, cigarette exposure, physical activity) and body mass index (BMI) related to the occurrence of vasomotor symptoms in perimenopausal and postmenopausal women?; and (2) Do lifestyle factors or BMI modify the effectiveness or side effects of menopausal hormone therapy (HT)? Information was culled from a nonstructured review of English-language literature. Moderate alcohol consumption (<1 drink per day for women) does not have a measurable effect on occurrence of vasomotor symptoms; whether greater amounts of alcohol intake would promote vasomotor symptoms cannot be addressed by available literature. Most published studies report that active cigarette smoking is positively associated with vasomotor symptoms. However, a large study found that passive (but not active) smoking (i.e., secondhand smoke exposure) was related to vasomotor symptoms. Studies to date do not support a relation between physical activity and vasomotor symptoms. However, rates of vasomotor symptom reporting were low in these studies, potentially limiting the ability to detect an effect of physical activity. Greater BMI is a risk factor for more vasomotor symptom reporting. The scarcity of data that directly address whether lifestyle factors or BMI modify the effects of HT precludes a substantive response to this question at present. Available literature suggests that smoking and higher body weight are risk factors for vasomotor symptoms; women with vasomotor symptoms who smoke may benefit from smoking cessation, and women who are heavier than ideal body weight may benefit from weight reduction. Whether certain behaviors or BMI raise or lower the risks or benefits of HT remains largely unknown and should be the focus of future research.

Lifestyle factors: are they related to vasomotor symptoms and do they modify the effectiveness or side effects of hormone therapy?

This article reviews and summarizes published literature in order to address the following questions: (1) Are lifestyle factors (alcohol use, cigarette exposure, and physical activity) and body mass index (BMI) related to the occurrence of vasomotor symptoms in perimenopausal and postmenopausal women? (2) Do lifestyle factors or BMI modify the effectiveness or side effects of menopausal hormone therapy (HT)? Information was culled from a nonstructured review of English-language literature. Low levels of alcohol consumption (< or =1 drink per day for women) do not have a measurable effect on occurrence of vasomotor symptoms; whether greater amounts of alcohol intake would promote vasomotor symptoms cannot be addressed by available literature. Most published studies report that active cigarette smoking is positively associated with vasomotor symptoms. However, a large study found that passive (but not active) smoking (i.e., secondhand smoke exposure) was related to vasomotor symptoms. Studies to date do not support a relation between physical activity and vasomotor symptoms. However, rates of vasomotor symptom reporting were low in these studies, potentially limiting the ability to detect an effect of physical activity. Greater BMI is a risk factor for more vasomotor symptom reporting. The scarcity of data that directly address whether lifestyle factors or BMI modify the effects of HT precludes a substantive response to this question at present. Available literature suggests that smoking and greater body weight are risk factors for vasomotor symptoms; women with vasomotor symptoms who smoke may benefit from smoking cessation, and women who are heavier than ideal body weight may benefit from weight reduction. Whether certain behaviors or BMI raise or lower the risks or benefits of HT remains largely unknown and should be the focus of future research.

Menopausal hormone therapy (HT) in patients with breast cancer

Objectives To assess the effect of menopausal hormone therapy (HT) on reoccurrence, cancer-related mortality, and overall mortality after a diagnosis of breast cancer. Methods We performed a quantitative review of all studies reporting experience with menopausal HT for symptomatic use after a diagnosis of breast cancer. Rates of reoccurrence, cancer-related mortality, and overall mortality were calculated in this entire group. A subgroup analysis was performed in studies using a control population to assess the odds ratio of cancer reoccurrence and mortality in hormone users versus non-users. Results Fifteen studies encompassing 1416 breast cancer survivors using HT were identified. Seven studies included a control group comprised of 1998 patients. Among the 1416 HT users, reoccurrence was noted in 10.0% (95% CI: 8.4–11.6%). Cancer-related mortality occurred at a rate of 2.6% (95% CI: 1.8–3.7%), while overall mortality was 4.5% (95% CI: 3.4–5.8%). Compared to non-users, patients using HT had a decreased chance of reoccurrence and cancer-related mortality with combined odds ratio of 0.5 (95% CI: 0.2–0.7) and 0.3 (95% CI: 0.0–0.6), respectively. Conclusions In our review, menopausal HT use in breast cancer survivors was not associated with increased cancer reoccurrence, cancer-related mortality or total mortality. Despite conflicting opinions on this issue, it is important for primary care physicians to feel comfortable medically managing the increasing number of breast cancer survivors. In the subset of women with severe menopausal symptoms, HT options should be reviewed if non-hormonal methods are ineffective. Future trials should focus on better ways to identify breast cancer survivors who may safely benefit from HT versus those who have a substantial risk of reoccurrence with HT use.

Effects of Estrogen With and Without Progestin on Urinary Incontinence

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). 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. 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. 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). 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. 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. 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.

Estrogen and progestin use and the QT interval in postmenopausal women.

To determine whether menopausal hormone therapy alters the QT interval in primarily healthy postmenopausal women. Despite well-known gender differences in myocardial repolarization that include a longer heart-rate-corrected QT interval (QT(C)) in women compared to men, the effects of menopausal hormone therapy on myocardial repolarization in women have not been well characterized. We studied 34,378 postmenopausal women participating in the dietary intervention component of the Women's Health Initiative. Cross-sectional associations were examined to assess possible effects of estrogen + progesterone on myocardial repolarization. Women who reported that they were never treated with menopausal hormone therapy (n = 12,451) were compared to women with a past use of menopausal hormone therapy (n = 3891), currently taking unopposed estrogen therapy (n = 9987), or combined current estrogen and progesterone therapy (n = 8049). Using analysis of covariance, the mean (+/-SEM) QT(C) interval was 423.1 +/- 0.2 milliseconds (ms) in those never treated with menopausal hormone therapy, 423.9 +/- 0.3 ms in past menopausal hormone therapy users, 425.6 +/- 0.2 ms in those currently on estrogen alone, and 424.0 +/- 0.2 ms in women currently on combined estrogen-progesterone therapy. Differences in mean QT(C) between those on estrogen alone and the other three groups were statistically significant. Comparisons of JT intervals, QT intervals, and linear corrected QT intervals among the groups yielded similar results. These results suggest that unopposed estrogen in menopausal women mildly prolongs myocardial repolarization, and the effect is reversed by progesterone. Whether these findings have clinical significance requires further study.

Comparison of angiographic findings among postmenopausal women using unopposed estrogen, estrogen/progestin combinations, and nonusers

Studies of the effects of menopausal hormone therapy on coronary artery disease (CAD) in postmenopausal women have provided contradictory results. Although recent experimental studies have revealed no beneficial effect of combination therapy with estrogen (E) and progesterone (P), the effect of monotherapy with E remains unknown. We retrospectively examined the medical records of 843 consecutive women aged ≥55 years who underwent their first cardiac catheterization between January 1996 and December 1998. We compared the presence and severity of CAD, defined as ≥1 diseased coronary vessel (with stenosis ≥50%), in women who only took E, E+P, or no menopausal hormone therapy. In all, 210 women (33%) took hormones, of whom 47 (22%) used E+P and 163 (78%) used E only. Women who used any hormones tended to be healthier than nonusers, but E+P users had a lower prevalence of risk factors and co-morbidities than E users. In unadjusted analyses, both the E and E+P groups were significantly less likely to have CAD than nonusers (relative risk [RR] 0.71, 95% confidence interval [CI] 0.58 to 0.84 for the E group; RR 0.76, 95% CI 0.54 to 0.99 for the E+P group). Demographic factors, CAD risk factors, co-morbidities, and primary prevention medication use explained the association between E+P and the presence of CAD (RR 1.14, 95% CI 0.74 to 1.39). In contrast, adjustment for these factors had a minimal effect on the association between E and CAD compared with nonusers (RR 0.79, 95% CI 0.59 to 0.98). Thus, the apparent protective effect of combination menopausal hormone therapy with E+P on CAD is due to differences in other patient characteristics. In contrast, unopposed E therapy may have a protective effect on CAD.

The discrepancy between observational studies and randomized trials of menopausal hormone therapy: did expectations shape experience?

Differences between observational and randomized studies of the effects of menopausal hormone therapy (HT) on coronary heart disease (CHD) have been attributed to the fact that women who choose to use HT tend to be healthier than those who do not. Although this bias should affect all clinical outcomes with modifiable risk factors, estimates for stroke and pulmonary embolism were unaffected. The authors sought possible explanations for this isolated discrepancy in CHD findings. Unlike the randomized Women's Health Initiative (WHI) trial, the observational Nurses' Health Study (NHS) did not try to detect silent myocardial infarctions. Many women present with atypical ischemic symptoms. Hormone therapy users who believe that HT reduces CHD risks might not interpret ischemic symptoms as related to CHD, might not seek medical attention, and might present differently to their physicians, all of which could lead to more unrecognized myocardial infarctions among HT users in the NHS. In addition, persons completing death certificates and NHS physicians interpreting death certificates were not blinded to the use of HT. If persons assigning cause of death knew the patient had used HT and believed that HT prevented CHD, they might have been more likely to assign a condition other than CHD as the cause of death. If HT users were 20% less likely to have their infarctions recognized and their deaths attributed to CHD, a true increase in CHD due to HT use would appear to be a reduction in CHD. Combining these reporting biases with socioeconomic differences between users and nonusers could explain discrepancies. Beliefs held by patients, clinicians, and investigators might have affected the ascertainment of CHD outcomes in observational studies.