Lynda F. Voigt

Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women

BACKGROUND Postmenopausal oestrogen therapy reduces the risk of osteoporosis and cardiovascular diseases but is associated with an increased risk of endometrial cancer. We have assessed the impact of a regimen of oestrogen with cyclic progestagen on risk of endometrial cancer for postmenopausal women. METHODS We did a population-based case-control study of women aged 45-74 years in western Washington State, USA. Cases were identified from a regional cancer registry as having histologically confirmed endometrial cancer during 1985-91. 832 (72%) of 1154 eligible cases completed interviews. Controls were identified by random digit dialling, screened for intact uterus, frequency matched for age and county, and randomly assigned a reference date within 1985-91. Interviews with 1114 (73%) of 1526 eligible controls were done. The women provided information about use of hormone replacement therapy, and reproductive and medical history before diagnosis date (cases) or reference date (controls). FINDINGS Relative to women who had never used hormones (for > 6 months), women who had taken unopposed oestrogen had a four-fold increase (95% CI 3.1-5.1) in risk of endometrial cancer. Women who used a combined therapy of oestrogen with cyclic progestagen (eg. medroxyprogesterone acetate) had a relative risk of 14 (1.0-1.9). Among women with fewer than 10 days of added progestagen per month, the relative risk was 3.1 (1.7-5.7). Whereas that for women with 10-21 days of added progestagen was 1.3 (0.8-2.2). The use of these combined regimens for 5 or more years was associated with risks of 3.7 (1.7-8.2) and 2.5 (1.1-5.5), respectively, relative to non-users of hormones. INTERPRETATION Postmenopausal women who use combined therapy of oestrogen with cyclic progestagen on a long-term basis have an increased risk of endometrial cancer compared with those who are not on hormone replacement, even when progestagen is added for 10 or more days per month. This increase is much smaller than that associated with unopposed oestrogen, but needs to be confirmed.

Progestagen supplementation of exogenous oestrogens and risk of endometrial cancer

The favourable effects of exogenous progestagen on the endometrium are well known, but have not been adequately quantified with respect to endometrial cancer. The benefits of progestagen need to be weighted against its possible untoward effects on the risk of breast cancer and cardiovascular disease. A population-based case-control study of endometrial cancer was undertaken to evaluate the benefits of progestagen use. 158 incident cases were identified between 1985 and 1987 among women aged 40-64 years who were residents of King County, Washington. Detailed interviews were conducted and the responses were compared with those of 182 controls selected by random telephone digit dialling. The risk of endometrial cancer among women who had used unopposed oestrogen for more than 3 years was over five times that of women who had used no hormones (relative risk [RR] 5.7, 95% confidence interval [Cl] 2.5-12.8), whereas those who had also used a progestagen for at least six months of that time had an RR of only 1.6 (95% Cl 0.6-3.9). The RR differed according to days per month that progestagen was used: 2.4 (0.6-9.3) for progestagen use of less than 10 days per month versus 1.1 (0.4-3.6) for use of 10 or more days per month. These results provide additional evidence that the use of progestagen for 10 or more days per cycle can reduce the excess risk of endometrial cancer associated with long-term postmenopausal oestrogen use.

Hormone replacement therapy regimens and breast cancer risk

OBJECTIVE Hormone replacement therapy (HRT) has increased in the United States over the past 2 decades in response to reports of long‐term health benefits. A relationship between HRT and breast cancer risk has been observed in a number of epidemiological studies. In 2002, the Womens Health Initiative Randomized Controlled Trial reported an association between continuous combined HRT and breast cancer risk. The objective of this study was to examine the association between breast cancer risk and HRT according to regimen and duration and recency of use. METHODS A multicenter, population‐based, case‐control study was conducted in five United States metropolitan areas from 1994 to 1998. Analyzed were data from 3823 postmenopausal white and black women (1870 cases and 1953 controls) aged 35–64 years. Odds ratios (ORs) were calculated as estimates of breast cancer risk using standard, unconditional, multivariable logistic regression analysis. Potential confounders were included in the final model if they altered ORs by 10% or more. Two‐sided P values for trend were computed from the likelihood ratio statistic. RESULTS Continuous combined HRT was associated with increased breast cancer risk among current users of 5 or more years (1.54; 95% confidence interval 1.10, 2.17). Additionally, a statistically significant trend indicating increasing breast cancer risk with longer duration of continuous combined HRT was observed among current users (P = .01). There were no positive associations between breast cancer risk and other HRT regimens. CONCLUSION Our data suggest a positive association between continuous combined HRT and breast cancer risk among current, longer term users. Progestin administered in an uninterrupted regimen may be a contributing factor. Risk dissipates once use is discontinued.

Relation of regimens of combined hormone replacement therapy to lobular, ductal, and other histologic types of breast carcinoma†

The incidence of invasive lobular carcinoma has been increasing among postmenopausal women in some parts of the United States. Part of this may be due to changes in classification over time. However, the use of combined (estrogen and progestin) hormone replacement therapy (CHRT) also has increased during the last decade and may account in part for the increase in invasive lobular breast carcinoma.

Diet and rheumatoid arthritis in women : A possible protective effect of fish consumption

&NA; Some researchers have hypothesized that omega‐3 fatty acids, found primarily in fish oils, may protect against the development of rheumatoid arthritis. We conducted a population‐based case‐control study in women, comparing 324 incident rheumatoid arthritis cases with 1,245 controls. We used a food frequency questionnaire to ascertain diet during a 1‐year period 5 years before a reference date (first physician visit for joint symptoms). Consumption of broiled or baked fish, but not of other types of fish, was associated with a decreased risk of rheumatoid arthritis. The adjusted odds ratios (OR) for 1‐<2 servings and ≥2 servings of broiled or baked fish per week, compared with <1 serving, were 0.78 [95% confidence interval (CI) = 0.53–1.14] and 0.57 (95% CI = 0.35–0.93). Other analyses showed associations with protein as a percentage of calories (adjusted OR for the top quartile as compared with the bottom quartile = 0.65; 95% CI = 0.46–0.94) and total calories (adjusted OR for the top quartile = 1.62; 95% CI = 1.15–2.28). The associations with broiled or baked fish, protein, and calories became stronger when we restricted our analysis to cases positive for rheumatoid factor. These results support the hypothesis that omega‐3 fatty acids may help prevent rheumatoid arthritis.

Menopausal hormone use and endometrial cancer, by tumor grade and invasion

We analyzed data from a population-based case-control study to investigate whether combined hormone replacement therapy influences the incidence of high-grade and -stage endometrial cancer. Subjects were women with epithelial endometrial cancer (N = 730) diagnosed during 1985-1991 and controls identified through random digit dialing (N = 1,002). Relative to hormone nonusers, women who took unopposed estrogens (mostly conjugated estrogens) for 3 or more years had a fivefold increase in the risk of tumors with myometrial invasion; the corresponding relative risk associated with combined therapy (estrogen and cyclic or continuous progestogen) for 3 or more years was only 1.3 (95% confidence interval = 0.8-2.2). We found a similar pattern of association for high-grade tumors.

Interindividual Variation in Nucleotide Excision Repair Genes and Risk of Endometrial Cancer

Exposure to estrogens is a likely cause of endometrial cancer, but the means by which estrogens exert this effect are not entirely clear. One hypothesis is that certain estrogen metabolites bind to the DNA, forming bulky adducts that damage the DNA and initiate carcinogenesis. A womans reduced capacity to repair such damage may increase her risk of endometrial cancer. We conducted a population-based case-control study in western Washington State to address the role of variation in nucleotide excision repair genes on the risk of endometrial cancer. Case women (n = 371), ages 50 to 69 years, were diagnosed with invasive endometrial cancer between 1994 and 1999. Control women (n = 420) were selected using random-digit dialing (ages 50-65 years) and by random selection from Health Care Financing Administration data files (ages 66-69 years). Genotyping assays were done for ERCC1, ERCC2 (XPD), ERCC4 (XPF), ERCC5 (XPG), XPA, and XPC. No appreciable differences between cases and controls were observed in the genotype distributions of ERCC1 (c8092a and c19007t), ERCC2 (D312N, K751Q, and c22541a), ERCC4 (R415Q and t30028c), or ERCC5 (D1104H). Carriage of at least one variant allele for XPA G23A was associated with decreased risk of endometrial cancer [odds ratio (OR), 0.70; 95% confidence interval (95% CI), 0.53-0.93]. Carriage of at least one XPC A499V variant allele was associated with a modest decrease in risk (OR, 0.79; 95% CI, 0.59-1.05). Women with variant alleles at both XPC A499V and K939Q had 58% of the risk of women with no XPC variant alleles (OR, 0.58; 95% CI, 0.35-0.96). Our data suggest that interindividual variation in XPA and XPC influences a womans risk of endometrial cancer.

Occurrence of breast cancer in relation to recreational exercise in women age 50-64 years

&NA; To investigate the relation between recreational physical activity and breast cancer, we conducted an analysis of a population‐based case‐control study of women age 50‐64 years in western Washington State. The study included 537 patients with breast cancer diagnosed during 1988‐1990 and 492 randomly selected population control women. Detailed information on recreational exercise habits and other risk factors for breast cancer was ascertained by structured in‐person interviews. A similar proportion of cases and controls reported exercise in the 2 years before the referent date (about 50%), or during ages 12‐21 years (about 40%). Compared with women who reported no exercise, there was a slightly decreased risk of breast cancer in women who exercised more than 1.5 hours per week in the 2 years before diagnosis (cases) or referent date (controls) [odds ratio (OR) = 0.7; 95% confidence interval (CI) = 0.4‐1.1], or who engaged in at least some high‐intensity exercise (OR = 0.7; 95% CI = 0.4‐1.1), but there was no clear decline in risk at the highest categories of duration or intensity. There was no association between any intensity exercise at ages 12‐21 years and risk of breast cancer. These results indicate a weak negative association between physical activity and risk of breast cancer in middle‐aged women.

Prostate carcinoma incidence in relation to prediagnostic circulating levels of insulin-like growth factor I, insulin-like growth factor binding protein 3, and insulin

There have been several epidemiologic studies investigating the association between circulating levels of insulin‐like growth factor I (IGF‐I), insulin‐like growth factor binding protein 3 (IGFBP‐3), and insulin in relation to the risk of prostate carcinoma, with conflicting results. To examine this issue further, the authors conducted a nested case–control study within the Cardiovascular Health Study cohort.

Risk of papillary thyroid cancer in women in relation to smoking and alcohol consumption

Both smoking and alcohol consumption may influence thyroid function, although the nature of these relations is not well understood. We examined the influence of tobacco and alcohol use on risk of papillary thyroid cancer in a population-based case-control study. Of 558 women with thyroid cancer diagnosed during 1988-1994 identified as eligible, 468 (83.9%) were interviewed; this analysis was restricted to women with papillary histology (N = 410). Controls (N = 574) were identified by random digit dialing, with a response proportion of 73.6%. We used logistic regression to calculate odds ratios (OR) and associated confidence intervals (CI) estimating the relative risk of papillary thyroid cancer associated with cigarette smoking and alcohol consumption. A history of ever having smoked more than 100 cigarettes was associated with a reduced risk of disease (OR = 0.7, 95% CI = 0.5-0.9). This reduction in risk was most evident in current smokers (OR = 0.5, 95% CI = 0.4-0.7). Women who reported that they had ever consumed 12 or more alcohol-containing drinks within a year were also at reduced risk (OR 0.7, 95% CI = 0.5-1.0). Similar to the association noted with smoking, the reduction in risk was primarily present among current alcohol consumers. The associations we observed, if not due to chance, may be related to actions of cigarette smoking and alcohol consumption that reduce thyroid cell proliferation through effects on thyroid stimulating hormone, estrogen, or other mechanisms.