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Polymorphisms within genes responsible for estrogen catabolism could alter cellular levels of genotoxic 4-hydroxylated catechol estrogens and antiangiogenic 2-methoxyestradiol, thus influencing risk of developing ovarian cancer. We carried out a population-based case-control study of 310 epithelial ovarian cancer cases and 585 controls in African-American and Caucasian women ages 35 to 54 years from Seattle, Atlanta, and Detroit metropolitan areas. Subjects were interviewed and genotyped for CYP1A1 m1, m2, m3, and m4; CYP1B1 Arg(48)Gly, Ala(119)Ser, Val(432)Leu, and Asn(453)Ser; COMT Val(158)Met; UGT1A1 A(TA)nTAA; and SULT1A1 Arg(213)His polymorphisms. Unconditional logistic regression was used to calculate odds ratios (OR). Haplotypes were inferred and analyzed using models based on expectation-maximization with progressive ligation and Bayesian coalescence theory. CYP1B1 Leu(432) carriers were at increased risk of ovarian cancer, with an adjusted OR of 1.5 (95% confidence interval, 1.1-2.3) compared with Val(432) homozygotes. The most common CYP1B1 haplotype was Arg(48)-Ala(119)-Val(432)-Asn(453). All other haplotypes with frequencies >5% contained the Leu(432) allele. In diplotype analyses, relative to women homozygous for Arg(48)-Ala(119)-Val(432)-Asn(453), women with diplotypes containing at least one Leu(432) allele had adjusted ORs ranging from 1.3 to 2.2. Among women homozygous for COMT Met(158), carriers of CYP1B1 Leu(432) had a 2.6-fold increase in risk relative to CYP1B1 Val(432) homozygotes (95% confidence interval, 1.1-5.9). This latter result is opposite in direction from a similar analysis conducted by other investigators in a different study population. No association of ovarian cancer risk was observed with any of the other polymorphisms examined, either alone or in combination.

Recent studies indicate that suppression of renal sympathetic nerve activity and attendant increments in renal excretory function are sustained baroreflex-mediated responses in hypertensive animals. Given the central role of the kidneys in long-term regulation of arterial pressure, we hypothesized that the chronic blood pressure-lowering effects of the baroreflex are critically dependent on intact renal innervation. This hypothesis was tested in 6 dogs by bilaterally activating the carotid baroreflex electrically for 7 days before and after bilateral renal denervation. Before renal denervation, control values for mean arterial pressure and plasma norepinephrine concentration were 95+/-2 mm Hg and 96+/-12 pg/mL, respectively. During day 1 of baroreflex activation, mean arterial pressure decreased 13+/-1 mm Hg, and there was modest sodium retention. Daily sodium balance was subsequently restored, but reductions in mean arterial pressure were sustained throughout the 7 days of baroreflex activation. Activation of the baroreflex was associated with sustained decreases in plasma norepinephrine concentration ( approximately 50%) and plasma renin activity (30% to 40%). All of the values returned to control levels during a 7-day recovery period. Two weeks after renal denervation, control values for mean arterial pressure, plasma norepinephrine concentration, plasma renin activity, and sodium excretion were comparable to those measured when the renal nerves were intact. Moreover, after renal denervation, all of the responses to activation of the baroreflex were similar to those observed before renal denervation. These findings demonstrate that the presence of the renal nerves is not an obligate requirement for achieving long-term reductions in arterial pressure during prolonged activation of the baroreflex.

In view of the effect of cholecystokinin (CCK) on dopaminergic neurons in the mesolimbic "reward" pathway of the brain, its gene has been a focus in studies of dopamine-related conditions and behaviors, including smoking. We assessed the association between the CCK C-45T polymorphism and smoking cessation among women who participated in a randomized clinical trial of d,l-fenfluramine conducted in the Seattle area in 1993-1994. Several years later (Mdn = 3.3 years, range = 2.4-6.9 years), 593 women provided a biological specimen and updated information about smoking habits. We defined short-term quitting as not smoking for at least 7 days immediately preceding the final (12-month) clinical trial visit, and long-term quitting as not smoking for at least the 6-month interval before the later recontact. CCK C-45T was not associated with either short-term (relative risk [RR] associated with the presence of T allele = 0.9, 95% CI = 0.6-1.4) or long-term (RR = 1.0, 95% CI = 0.6-1.5) smoking cessation. Also, we observed no association of this polymorphism with smoking cessation in subgroups of women defined by age or body mass index. No clear differences were found in smoking cessation rates associated with the presence of the T allele among women treated with d,l-fenfluramine versus those randomized to placebo. Our results fail to support prior evidence of an association of the CCK C-45T polymorphism with the ability to quit smoking.

Background: Breast cancer patients with tumors that are estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive have lower risks of mortality after their diagnosis compared to women with ER- and/or PR-negative disease. However, few studies have evaluated variations in the risks of breast cancer-specific mortality across ER/PR status by either demographic or clinical characteristics., Methods: Using data from 11 population-based cancer registries that participate in the SEER (Surveillance, Epidemiology, and End Results) program, 155,175 women at least 30 years old with a primary diagnosis of invasive breast carcinoma from 1990 to 2001 were included in the study. Associations between joint hormone receptor status and breast cancer mortality risk within categories of diagnosis age, diagnosis year, race/ethnicity, histologic tumor type, stage, grade, size, and axillary lymph node status were evaluated using the Cox proportional hazards model., Results: Compared to ER+/PR+ cases, elevations in risk of mortality were observed across all subcategories of age at diagnosis, ranging from 1.2- to 1.5-fold differences for ER+/PR- cases, 1.5- to 2.1-fold differences for ER-/PR+ cases, and 2.1- to 2.6-fold differences for ER-/PR- cases. Greater differences were observed in analyses stratified by grade; among women with low-grade lesions, ER-/PR- patients had a 2.6-fold (95% confidence interval [CI] 1.7 to 3.9) to 3.1-fold (95% CI 2.8 to 3.4) increased risk of mortality compared to ER+/PR+ patients, but among women with high-grade lesions, they had a 2.1-fold (95% CI 1.9 to 2.2) to 2.3-fold (95% CI 1.8 to 2.8) increased risk., Conclusion: Compared to women with ER+/PR+ tumors, women with ER+/PR-, ER-/PR+, or ER-/PR- tumors experienced higher risks of mortality, which were largely independent of the various demographic and clinical tumor characteristics assessed in this study. The higher relative mortality risks identified among ER-/PR- patients with small or low-grade tumors raise the question of whether there may be a beneficial role for adjuvant chemotherapy in this population.

Inflammation and oxidative stress have been implicated as pathogenic mechanisms in Parkinson's disease (PD). Evidence from in vitro and animal studies suggests a possible protective role of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin. We investigated the risk of PD associated with use of aspirin and nonaspirin NSAIDs in a population-based case-control study among enrollees of Group Health Cooperative, a health maintenance organization in the Seattle area. Subjects included 206 cases between ages 35 and 89 with a new diagnosis of idiopathic PD between 1992 and 2002, and 383 randomly selected controls frequency-matched by age, sex, duration of enrollment, and clinic. We obtained information on participants' age, smoking, and medical history from interview. Exposure to NSAIDs was ascertained from an automated pharmacy database. Medications filled within 5 years of the interview were excluded. After adjusting for age, sex, smoking, duration of enrollment, and clinic, the risk of PD among individuals who received nonaspirin NSAIDs between 1977 and 1992 was 0.90 (95% CI: 0.59-1.35) and 1.67 (95% CI: 0.60-4.60) between 1993 and 2002. Use of ibuprofen was not associated with PD (OR: 0.89; 95% CI: 0.60-1.32). The risk of PD associated with aspirin or aspirin-containing medications was 0.74 (95% CI: 0.49-1.12). We observed no trend in risk according to number of fills for these drugs. Our results provide only limited support for the hypothesis that use of aspirin may reduce the risk of this disease, and no indication of protection from other NSAIDs., ((c) 2006 Movement Disorder Society.)

Objective: We conducted a population-based case-control study of epithelial ovarian cancer in relation to measures of body size and adult weight change. In particular, we sought to characterize the independent relation of body weight at particular ages with risk., Methods: In-person interviews were sought with 35-54 year-old female residents of metropolitan Atlanta, Seattle or Detroit diagnosed with ovarian cancer during 1994-1998, and with controls sampled from these populations. Information provided by 355 cases and 1,637 controls was analyzed using unconditional logistic regression., Results: The risk among women in the top tenth, relative to women in the lowest fourth, of the distribution of body weight at age 18 years was 1.5 (95% confidence interval, 1.0-2.2); at age 30, 1.9 (1.2-2.9); and 5 years before the reference date, it was 2.1 (1.4-3.3). While our results did not substantiate risk elevations reported in previous studies among subsets of women (e.g., with particular histologic tumor subtypes or according to past oral contraceptive use), we noted a particularly increased risk among women who reported 10 or more pounds gained during their first year of oral contraceptive use., Conclusions: Our findings suggest that risk of epithelial ovarian cancer may be most closely linked with body weight in the relatively recent past (but before the time in which the disease may manifest as weight loss) among women who develop this disease during the years before or shortly after menopause.

Although associations have been reported between antidepressant use and risk of breast cancer, the findings have been inconsistent. We conducted a population-based case-control study among women enrolled in Group Health Cooperative (GHC), a health maintenance organization in Washington State. Women with a first primary breast cancer diagnosed between 1990 and 2001 were identified (N = 2904) and five controls were selected for each case (N = 14396). Information on antidepressant use was ascertained through the GHC pharmacy database and on breast cancer risk factors and screening mammograms from GHC records. Prior to one year before diagnosis of breast cancer, about 20% of cases and controls had used tricyclic antidepressants (adjusted odds ratio = 1.06, 95% CI 0.94-1.19) and 6% of each group had used selective serotonin reuptake inhibitors (OR = 0.98, 95% CI 0.80-1.18). There also were no differences between cases and controls with regard to the number of prescriptions filled or the timing of use. Taken as a whole, the results from this and other studies to date do not indicate an altered risk of breast cancer associated with the use of antidepressants overall, by class, or for individual antidepressants.

Despite recent evidence indicating sustained activation of the baroreflex during chronic infusion of angiotensin II (Ang II), sinoaortic denervation does not exacerbate the severity of the hypertension. Therefore, to determine whether Ang II hypertension is relatively resistant to the blood pressure-lowering effects of the baroreflex, the carotid baroreflex was electrically activated bilaterally for 7 days in 5 dogs both in the presence and absence of a continuous infusion of Ang II (5 ng/kg per minute) producing high physiological plasma levels of the peptide. Under control conditions, basal values for mean arterial pressure (MAP) and plasma norepinephrine concentration (NE) were 93+/-1 mm Hg and 99+/-25 pg/mL, respectively. By day 7 of baroreflex activation, MAP and NE were reduced to 72+/-4 mm Hg (-21+/-3 mm Hg) and 56+/-15 pg/mL, respectively, but PRA was unchanged (control=0.41+/-0.06 ng ANG I/mL per hour). All values returned to basal levels by the end of a 7-day recovery period. After 7 days of Ang II infusion, MAP increased from 93+/-3 to 129+/-3 mm Hg, whereas NE fell from 117+/-15 to 86+/-23 pg/mL. During the next 7 days of baroreflex activation/Ang II infusion, further reductions in NE were not statistically significant, and on the final day of baroreflex activation, the reduction in MAP was only 5+/-1 mm Hg, compared with 21+/-3 mm Hg in the control normotensive state. These findings indicate that long-term baroreflex-mediated reductions in arterial pressure are markedly diminished, but not totally eliminated, in the presence of hypertension produced by chronic infusion of Ang II.

2-Hydroxylated metabolites of estrogen have been shown to have antiangiogenic effects and inhibit tumor cell proliferation, whereas 4-hydroxylated metabolites have been implicated in carcinogenesis. We examined whether polymorphisms in certain genes involved in estrogen metabolism are associated with endometrial cancer risk in a population-based case-control study with 371 cases and 420 controls. Based on previously published genotype-phenotype correlation studies, we defined variant alleles thought to increase estrogen 2-hydroxylation as presumptively low-risk (CYP1A1 m1 T6235C and m2 Ile(462)Val) and those thought to increase estrogen 4-hydroxylation as high-risk (CYP1A1 m4 Thr(461)Asn, CYP1A2 A734C, and CYP1B1 Leu(432)Val). Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression. Carrying at least one CYP1A1 m1 or m2 variant allele was associated with a decreased risk of endometrial cancer [ORs (95% CIs), 0.64 (0.44-0.93) and 0.54 (0.30-0.99), respectively]. No strong alteration in risk was observed among women with any of the putative high-risk alleles. When CYP1A1, CYP1A2, and CYP1B1 genotypes were combined and ranked by the number of putative low-risk genotypes carried, women with four or five low-risk genotypes had a reduced risk of endometrial cancer (OR, 0.29; 95% CI, 0.15-0.56) compared with women with one or none. No appreciable alteration in risk was observed among women carrying two or three low-risk genotypes. Some of our findings are consistent with the hypothesis that increased estrogen 2-hydroxylation is associated with decreased endometrial cancer risk, but replication of these results is required before any firm conclusions can be reached.

The authors conducted a population-based, case-control study among women aged 35-54 years to assess the influence of infertility and use of ovulation-inducing drugs on ovarian cancer risk. The study was conducted from 1994 to 1998 in three regions (metropolitan Atlanta, Georgia, Detroit, Michigan, and Seattle, Washington) and included 378 cases and 1,637 controls. Data were obtained through in-person interviews, and analysis was conducted using unconditional logistic regression. Among parous women, the authors observed no association of cancer risk with a history of infertility, medical evaluation for infertility, specific types of infertility, or use of ovulation-inducing drugs. Among nulliparous women, risk was increased among women with a history of infertility (odds ratio = 1.6, 95% confidence interval: 1.0, 2.6), particularly when infertility first became manifest relatively late in reproductive life (for first infertility at > or =30 years of age: odds ratio = 2.2, 95% confidence interval: 1.1, 4.5); risk was not associated with medical evaluation for infertility, specific types of infertility, or use of ovulation-inducing drugs. Findings were similar when borderline and invasive epithelial tumors were considered separately. While the results of this study support the hypothesis that a subset of nulliparous women who experience infertility may be at increased risk of ovarian cancer, the reasons for this increase in risk remain unclear.

The role of baroreflexes in long-term control of arterial pressure is unresolved. To determine whether chronic activation of the baroreflex produces sustained hypotension, we developed a method for prolonged activation of the carotid baroreflex in conscious dogs. This was achieved by chronically implanting electrodes around both carotid sinuses and using an externally adjustable pulse generator to electrically activate the carotid baroreflex. Control values for mean arterial pressure (MAP) and heart rate were 93+/-3 mm Hg and 64+/-4 bpm, respectively. After control measurements, the carotid baroreflex was activated bilaterally for 7 days at a level that produced a prompt and substantial reduction in MAP, and for day 1 MAP was reduced to 75+/-4 mm Hg. Moreover, this hypotensive response was sustained throughout the entire 7 days of baroreflex activation (day 7, MAP=72+/-5 mm Hg). During prolonged baroreflex activation, heart rate decreased in parallel with MAP, although the changes were not as pronounced (day 7, heart rate=51+/-3 bpm). Prolonged baroreflex activation was also associated with approximately 35% reduction in plasma norepinephrine concentration (control=87+/-15 pg/mL). After baroreflex activation, hemodynamic measures and plasma levels of norepinephrine returned to control levels. Interestingly, despite the pronounced fall in MAP, plasma renin activity did not increase during prolonged baroreflex activation. These data indicate that prolonged baroreflex activation can lead to substantial reductions in MAP by suppressing the sympathetic nervous system. Furthermore, sustained sympathoinhibitory effects on renin secretion may play an important role in mediating the long-term hypotensive response.

We conducted two studies to evaluate the hypothesis that late age at first exposure to a common infectious agent such as Epstein-Barr virus (EBV) may be related to the risk of developing epithelial ovarian cancer. Because EBV more commonly results in infectious mononucleosis (IM) when primary infection occurs at a late age, we first assessed risk associated with age at IM in a population-based case-control study using unconditional logistic regression to estimate odds ratios and their 95% confidence intervals. Risk of ovarian cancer was 0.0, 0.9, 1.5, and 2.1 among women diagnosed with IM at < 15, 15-19, 20-24, and > 24 years, respectively, relative to women never diagnosed with IM (p for trend among women with IM = 0.02). In a second study, we examined EBV antibody titers among an independent sample of ovarian cancer cases and controls. Women with elevated IgG titers to viral capsid antigen, a marker of a relatively severe (and, conceivably, later) initial EBV infection, had a 5.3-fold (95% CI 1.5-18.4) increased risk of ovarian cancer. Together, these two studies provide some support for the hypothesis that late age at primary infection with a common agent (conceivably, EBV) may play a role in the etiology of ovarian cancer.

Objective: An increased risk of ovarian cancer among users of antidepressants and benzodiazepines has been observed in some but not all prior studies. We examined these associations in a population-based case-control study., Methods: We identified 314 members of a health maintenance organization (HMO) who were diagnosed with epithelial ovarian cancer between 1981 and 1997, were aged 35-79 years at diagnosis, and had at least 4 years of HMO membership. Up to four controls were selected for each case (n = 790), matched on age, calendar year, and length of HMO membership. Information concerning past medication use was obtained from the computerized pharmacy database, established in 1977., Results: Cases were slightly less likely than controls to have filled two antidepressant prescriptions (primarily for doxepin, amitriptyline, or imipramine) in any 6-month period prior to a reference date set 1.5 years before diagnosis (conditional odds ratio (OR) 0.71, 95% confidence interval (CI) 0.47-1.1), or to have used an antidepressant continuously for 6 months or longer (OR 0.64, 95% CI 0.36-1.1). Cases were less likely than controls to have filled two benzodiazepine prescriptions in 6 months (OR 0.70, 95% CI 0.47-1.0) or to have used benzodiazepines continuously for 6 months or longer (OR 0.53, 95% Cl 0.15-1.9)., Conclusions: Our findings suggest that there is not an increased risk of ovarian cancer in women who have taken some types of antidepressants or benzodiazepines.

Objective: Exercise has been hypothesized to influence cancer risk through a variety of mechanisms including hormonal, metabolic and immunologic effects, yet its relation with the risk of thyroid cancer has not been examined. We conducted a population-based case-control study in women aged 18-64 in three counties of western Washington State to assess the relation of recreational physical activity with risk of papillary thyroid cancer., Methods: Of 558 women with thyroid cancer of the follicular epithelium diagnosed during 1988-1994 who were 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%. Logistic regression was used to calculate odds ratios (OR) and associated confidence intervals (CI) estimating the relative risk of papillary thyroid cancer associated with various aspects of recreational exercise., Results: Risk of thyroid cancer was reduced among women who reported that they engaged in regular recreational exercise during the 2 years before diagnosis relative to women who did not report exercise during that time period (OR = 0.76, 95% CI 0.59-0.98). A similar risk reduction was noted among women who reported having exercised regularly between ages 12 and 21 (OR = 0.83, 95% CI 0.64-1.1). However, no clear associations with aspects of recreational activity, including average hours exercised per week or weekly energy expenditure, were observed., Conclusions: These results provide some initial support for the hypothesis that physical activity may reduce risk of thyroid cancer.

The fetal antigen hypothesis suggests that the lowered risk of breast cancer in parous women may be afforded by the development of antibodies to fetal antigens that are structurally similar to mammary cancer antigens. It has previously been hypothesized that the likelihood of developing such antibodies may be higher among women who have had children with more than 1 partner. Utilizing information on parenthood and breast cancer available in nationwide Swedish registers, we undertook a case-control study nested within a nation-wide cohort to address this issue. Number of partners fathering a child was categorized as 1, 2 and 3 or more. All analyses were restricted to subjects with 2 or more births and encompassed a total of 20,881 women with breast cancer and 111,989 control women. In an unadjusted analysis, the risk of breast cancer was somewhat lower (odds ratio [OR] = 0.94, 95% confidence interval [CI] 0.89-0.99) in women who had had children with 2 different partners compared with women who had had children conceived with the same partner. After adjustment for parity, age at first birth and educational level, however, the risk of breast cancer was slightly elevated (OR = 1.09, 95% CI: 1.03-1.15). Among women who had had children with 3 or more different men, the pattern was similar. The present results provide no support for the hypothesis that greater antigenic exposure afforded by having children with more than 1 man may reduce the risk of breast cancer. It remains possible, however, that pregnancy may influence breast cancer risk through some immunologic mechanism; further testing of the fetal antigen hypothesis may require development of relevant laboratory measures., (Copyright 2001 Wiley-Liss, Inc.)

The familial form of nonmedullary thyroid carcinoma (NMTC) is a complex genetic disorder characterized by multifocal neoplasia and a higher degree of aggressiveness than its sporadic counterpart. In a large Tasmanian pedigree (Tas1) with recurrence of papillary thyroid carcinoma (PTC), the most common form of NMTC, an extensive genomewide scan revealed a common haplotype on chromosome 2q21 in seven of the eight patients with PTC. To verify the significance of the 2q21 locus, we performed linkage analysis in an independent sample set of 80 pedigrees, yielding a multipoint heterogeneity LOD score (HLOD) of 3.07 (alpha=0.42), nonparametric linkage (NPL) 3.19, (P=.001) at marker D2S2271. Stratification based on the presence of at least one case of the follicular variant of PTC, the phenotype observed in the Tas1 family, identified 17 such pedigrees, yielding a maximal HLOD score of 4.17 (alpha=0.80) and NPL=4.99 (P=.00002) at markers AFMa272zg9 and D2S2271, respectively. These results indicate the existence of a susceptibility locus for familial NMTC on chromosome 2q21.

Background: Hormone replacement therapy (HRT) is typically avoided for women with a history of breast cancer because of concerns that estrogen will stimulate recurrence. In this study, we sought to evaluate the impact of HRT on recurrence and mortality after a diagnosis of breast cancer., Methods: Data were assembled from 2755 women aged 35-74 years who were diagnosed with incident invasive breast cancer while they were enrolled in a large health maintenance organization from 1977 through 1994. Pharmacy data identified 174 users of HRT after diagnosis. Each HRT user was matched to four randomly selected nonusers of HRT with similar age, disease stage, and year of diagnosis. Women in the analysis were recurrence free at HRT initiation or the equivalent time since diagnosis. Rates of recurrence and death through 1996 were calculated. Adjusted relative risks were estimated by use of the Cox regression model. All statistical tests were two-sided., Results: The rate of breast cancer recurrence was 17 per 1000 person-years in women who used HRT after diagnosis and 30 per 1000 person-years in nonusers (adjusted relative risk for users compared with nonusers = 0.50; 95% confidence interval [CI] = 0.30 to 0.85). Breast cancer mortality rates were five per 1000 person-years in HRT users and 15 per 1000 person-years in nonusers (adjusted relative risk = 0.34; 95% CI = 0.13 to 0.91). Total mortality rates were 16 per 1000 person-years in HRT users and 30 per 1000 person-years in nonusers (adjusted relative risk = 0.48; 95% CI = 0.29 to 0.78). The relatively low rates of recurrence and death were observed in women who used any type of HRT (oral only = 41% of HRT users; vaginal only = 43%; both oral and vaginal = 16%). No trend toward lower relative risks was observed with increased dose., Conclusion: We observed lower risks of recurrence and mortality in women who used HRT after breast cancer diagnosis than in women who did not. Although residual confounding may exist, the results suggest that HRT after breast cancer has no adverse impact on recurrence and mortality.

Parallel to its established causal association with both infectious mononucleosis (IM) and young adulthood Hodgkin disease (YAHD), we propose a hypothesis that "delayed" primary EBV infection (i.e., primary infection occurring during adolescence or adulthood) is associated with elevated breast cancer risk. We evaluated this hypothesis with two investigations, one descriptive and the other analytic. The descriptive study used international/United States cancer registry data to assess the association between incidence rates of breast cancer and those of YAHD. The incidence rates of the seemingly unrelated neoplasms were strongly correlated (correlation coefficients of 0.74 and 0.88 for international and United States data, respectively; these were higher than the correlation coefficients of YAHD with two other cancers that we considered). Populations with higher incidence rates corresponded to those with higher likelihood of delayed primary EBV infection. The analytical study was based on a population-based case-control study of breast cancer in middle-aged women. Age-adjusted odds ratios of breast cancer in women who reported a history of IM, relative to women who did not, increased monotonically from 0.55 [95% confidence interval (CI), 0.05-6.17] for women with 0-9 years of age at IM onset to 2.67 (CI, 1.04-6.89) for women with > or =25 years of age at IM onset (P = 0.016). An older age at tonsillectomy, another surrogate of delayed EBV exposure, was also associated with increased risk of breast cancer: odds ratios, 0.92 (CI, 0.57-1.48) and 1.76 (CI, 1.15-2.69) for women with tonsillectomy at 0-4 years of age and > or =15 years of age, respectively (P = 0.018). Adjusting for additional potential confounders did not modify the associations appreciably. The implications of the findings and a potential biological mechanism are presented.

Background: Breast and thyroid cancer have been observed to occur more frequently than expected as multiple primary tumors in women. The study presented herein focuses on the effects of age at diagnosis and treatment for the first cancer on the development of the second cancer., Methods: This retrospective cohort study used a study population consisting of 38,632 women diagnosed with primary invasive breast cancer and 2189 women diagnosed with primary invasive thyroid cancer between 1974 and 1994. Cases were identified from records of the Cancer Surveillance System of western Washington and followed for subsequent cancer development through 1995., Results: Seventy-one women were diagnosed during their lives with both breast and thyroid cancers. Including cancers diagnosed during the same month as or after the initial cancer, the relative risk (RR) of breast cancer among women with thyroid cancer was 1.5 (95% confidence interval [CI] 1.1-2.0), and the RR of thyroid cancer among women with breast cancer was 1.5 (95% CI 1.1-2.2). Among women with thyroid cancer, risk of breast cancer was greatest when the latter cancer was diagnosed under 45 years of age (RR = 2.3, 95% CI 1.1-4.4). First course of treatment, including radiation or hormonal therapy to treat thyroid cancer, and radiation, chemotherapy, or hormonal therapy to treat breast cancer, did not alter a woman's risk of developing the second cancer., Conclusions: The data suggest that the incidence of breast and thyroid cancer may be related, and that in particular women with thyroid cancer may be at a moderately increased risk of developing breast cancer before age 45.

Objective: To identify dietary and environmental risk factors for hyperthyroidism in cats., Design: Case-control study., Animals: 100 cats with hyperthyroidism and 163 control cats., Procedure: Medical records were examined, and owners completed a mailed questionnaire. Data collected included information regarding demographic variables, environmental exposures, and diet, including preferred flavors of canned cat food., Results: Case cats were significantly less likely to have been born recently than control cats. Housing; exposure to fertilizers, herbicides, or plant pesticides; regular use of flea products; and presence of a smoker in the home were not significantly associated with an increased risk of disease, but cats that preferred fish or liver and giblets flavors of canned cat food had an increased risk., Conclusions and Clinical Relevance: Results suggest that cats that prefer to eat certain flavors of canned cat food may have a significantly increased risk of hyperthyroidism.

The authors conducted a population-based case-control study of 410 women residing in three counties in western Washington State who were aged 18-64 years when diagnosed with papillary thyroid cancer in 1988-1994 and 574 controls to assess the effects of pregnancy history and other aspects of reproductive life on risk of this disease. Among women aged 45-64, the authors observed no associations with number of live births, age at first live birth, or age at last live birth. Risk was somewhat increased in women <45 years who had given birth within the previous 5 years; this association was most evident among women who reported that cancer symptoms had led to diagnosis. Among women who had given birth within the last 5 years, risk was greatest among those with two or more births during that time period (relative risk (RR) = 4.2, 95% confidence interval (CI): 2.0, 8.9, relative to parous women whose last birth was >5 years before the reference date). Risk of thyroid cancer was also associated with lactation during the previous 5 years (e.g., RR = 2.9, 95% CI: 1.5, 5.5, among parous women who had breastfed > or =12 months, vs. 0-1 months, during that interval). Our results suggest that thyroid stimulation during both pregnancy and lactation may result in a transient increase in risk of papillary thyroid cancer.

Histamine (H2) receptor antagonists, such as cimetidine and ranitidine, became available in the late 1970s and presently number among the most commonly used drugs. Cimetidine has been hypothesized to exert a cancer preventive effect on the prostate due to its ability to inhibit the binding of dihydrotestosterone to androgen receptors. Other hormonal effects of this drug include increases in serum prolactin levels and inhibition of 2-hydroxylation of estradiol. We assessed risk of prostate and breast cancers in a cohort of 48,512 members of the Group Health Cooperative of Puget Sound prescribed cimetidine or another H2 blocker between 1977 and 1995. Standardized incidence ratios were calculated comparing the observed numbers of cancers to those expected based on population rates in western Washington State. Because cimetidine, but not other H2 blockers, influences hormonal activity and metabolism, we conducted nested case-control studies comparing cancer risk among individuals treated with cimetidine to individuals who used other H2 blockers. Risks of breast and prostate cancers were identical among users of cimetidine and users of other H2 blockers (relative risk, 1.0 for both cancers). We observed no trend in risk of breast cancer according to time since first or last cimetidine prescription or number of cimetidine prescriptions filled. For prostate cancer, our findings were similar save for a modest increase in risk among men who had filled > or =21 cimetidine prescriptions (relative risk, 1.4; 95% confidence interval, 1.0-1.9). Our results suggest that use of cimetidine does not influence risk of female breast cancer. Further, these data provide little evidence to support the previously hypothesized preventive effect of cimetidine on risk of prostate cancer.

The hypothesis that a woman's immunologic response to fetal antigens arising from paternal genes may explain some of the reduction in risk of ovarian cancer associated with parity has not, to our knowledge, been examined. We analyzed data from a case-control study to evaluate the risk of epithelial ovarian cancer among women of similar parity associated with proposed indices of paternally derived fetal antigen exposure. Cases included white women 20-79 years of age diagnosed with epithelial ovarian cancer in three counties in Washington State between January 1, 1986, and December 31, 1988 (N = 322). Controls (N = 426) were selected by random-digit dialing and were broadly similar to cases in age and county of residence. After excluding women who had fewer than two pregnancies (or, in some analyses, fewer than two livebirths) and adjusting for age and number of livebirths, we observed no reduction in risk associated with number of marriages or number of partners with whom a study participant conceived a pregnancy and/or had a child. Nevertheless, these relatively crude indices of exposure to paternally derived fetal antigens do not preclude the possibility that a woman's response to other fetal or pregnancy-related antigens may antagonize the development of ovarian cancer.

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.

We evaluated reproductive risk factors for mucinous and non-mucinous tumors in a population-based case-control study of epithelial ovarian cancer among women ages 20-79 years. We observed a reduction in risk of tumors of both types in association with one or more full-term pregnancies and with use of oral contraceptives for 5 or more years. While findings of some previous studies support the hypothesis that certain aspects of a woman's reproductive life have a different impact on the risk of these subtypes of ovarian epithelial cancer, our data suggest that this issue is not yet resolved.

One striking paradox in epidemiologic research is the strong association between diet and cancer in ecologic studies compared with the weaker associations reported in many within-country case-control and cohort studies. However, most ecologic studies have relied on indirect measures of dietary intake, such as food disappearance data. The objectives of our study were to assess the feasibility of collecting dietary and biomarker data from individuals living in countries having markedly different dietary patterns and cultures and to examine the magnitude of the between-country variation in their measurement. Adults surveyed in Shanghai (China), Costa Rica and King County (Washington, USA) completed a 24-hr dietary recall, a cancer risk factor survey, and provided a blood sample. We analyzed a subset of the blood specimens for vitamins C, E, carotenoids and phospholipid fatty acids. We observed substantial differences in nutrient intakes and in mean plasma concentrations of dietary biomarkers across the study populations. For example, King County participants had the highest daily intake of vitamin C (mean 78.3 +/- 12.2 mg compared with 42.6 +/- 38.3 mg in Shanghai and 34.8 +/- 43.8 mg in Costa Rica). The mean plasma vitamin C level in King County was also the highest of the 3 study sites: 927.9 +/- 43.9 microg/dl in King County, 585.7 +/- 35.9 microg/dl in Shanghai and 461.1 +/- 33.1 microg/dl in Costa Rica. Plasma trans fatty acids (a biomarker of a diet high in hydrogenated fats) were highest in King County and lowest in Shanghai.

Twin studies consistently indicate important genetic influences on multiple aspects of smoking behavior, including both initiation and cessation; however, knowledge regarding the role of specific genes is extremely limited. Habit-forming actions of nicotine appear to be triggered primarily at nicotinic receptors on the cell bodies of dopaminergic neurons in the mesolimbic "reward" system of the brain, a region implicated in addiction to other substances including cocaine, opiates, and alcohol. Important aspects of the dopaminergic pathway include synthesis of dopamine in dopaminergic neurons, release of dopamine by presynaptic neurons, receptor activation of postsynaptic neurons, dopamine re-uptake by presynaptic neurons, and metabolism of released dopamine. Research examining the role of allelic variation in genes involved in these functions is being actively pursued with respect to addictive behavior as well as personality traits and psycho- and neuropathologic conditions and has implications for smoking research. In addition, genetic differences in nicotinic receptors or nicotine metabolism might reasonably be hypothesized to play a role in smoking addiction. A role of dopaminergic or other genes in smoking cessation is of particular potential importance, as research in this area may lead to the identification of subgroups of individuals for whom pharmacologic cessation aids may be most effective.

Objectives: Late age at first birth and nulliparity are established risk factors for breast cancer, yet the extent to which fertility problems contribute to these associations remains largely unexplored. Here, we examine self-reported fertility problems as a risk factor for breast cancer in young women., Methods: We used a population-based case-control study of 2,173 cases and 1,990 controls aged 20 to 54 years in the United States. Structured in-person interviews were used to elicit detailed information on established and potential breast cancer risk factors. Information was collected on pregnancy details, including difficulties becoming pregnant or maintaining a pregnancy., Results: Self-reported difficulty in becoming pregnant or maintaining a pregnancy was reported by 450 cases and 377 controls. Overall, there was little association between these fertility problems and risk of breast cancer (odds ratio [OR] = 1.05). Parity was associated with a decreased risk of breast cancer in women both with (OR = 0.71) and without (OR = 0.79) fertility problems. There was little evidence of an increased risk of breast cancer with later age at first full-term birth among women without fertility problems (ORage 35+ :age <20 = 1.13, 95 percent confidence interval [CI] = 0.7-1.9), but a relatively strong association among women with fertility problems (ORage 35+ :age <20 = 2.96, CI = 1.3-7.0). Among women with a first full-term birth at age 35 or older, fertility problems were associated with a twofold risk of breast cancer. Analyses of duration of unprotected sexual intercourse prior to first pregnancy as an alternative estimate of infertility produced similar results., Conclusions: Our study suggests that the association between late age at first birth and breast cancer is stronger among women with self-reported fertility problems than among women with no fertility problems.

Objectives: Greater incidence of thyroid cancer in women than men, particularly evident during the reproductive years, has led to the suggestion that female hormones may increase risk of this disease. We conducted a population-based case-control study in women aged 18 to 64 years in three counties of western Washington State (United States) to assess the relation of use of exogenous hormones, including oral contraceptives (OC) and hormone replacement therapy (HRT), to risk of papillary thyroid cancer., Methods: Of 558 women with thyroid cancer of the follicular epithelium diagnosed during 1988-94 who were identified as eligible, 468 (83.9 percent) 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 percent. Logistic regression was used to calculate odds ratios (OR) and associated 95 percent confidence intervals (CI) estimating the relative risk of papillary thyroid cancer among users of exogenous hormones., Results: Among women aged 45 to 64 years, we observed no association of use of OCs or HRT with risk of papillary thyroid cancer. Among women less than 45 years of age, risk of papillary thyroid cancer was reduced in women who had ever used OCs (OR = 0.6, CI = 0.4-0.9); beyond the relation with ever-use, there was no further association with specific aspects of exposure such as estrogenic potency, latency, recency, age at first or last use, or use at the reference date., Conclusions: Our data do not support the hypothesis that use of exogenous estrogens increases the risk of female thyroid cancer.

Background: Information is limited on the risk of contralateral breast cancer after a diagnosis of breast carcinoma in situ (BCIS)., Methods: In western Washington, between 1974 and 1993, 1929 women with a first primary ductal carcinoma in situ (DCIS) and 282 women with a first primary lobular carcinoma in situ (LCIS) were followed for contralateral breast cancer. Rates of contralateral invasive breast cancer and BCIS were compared with population rates of first primary breast cancer using Poisson regression to adjust for age and calendar year., Results: The rate of contralateral invasive disease after BCIS was approximately twice the population rate for women with DCIS and three times the population rate for women with LCIS; relative rates decreased somewhat with increasing time since diagnosis of LCIS, but were fairly stable after DCIS. The relative rate of contralateral DCIS after BCIS was substantially higher than for contralateral invasive disease, but dropped dramatically after the first year after the initial BCIS, especially among women with LCIS. Contralateral BCIS usually was of the same histologic type as the initial BCIS; histologic concordance of BCIS was 71% for women with an initial LCIS and 78% for women with DCIS., Conclusions: Data suggest that the rate of contralateral invasive breast cancer is elevated for at least 5 years after a diagnosis of BCIS compared with the rate of first primary breast cancer in the population, and that the rate is only slightly higher for women with LCIS than for women with DCIS. The markedly elevated rate of contralateral DCIS may result in large part from increased medical surveillance of women diagnosed with BCIS, especially during the first year after the initial diagnosis.

Previously we proposed an aggregate data study design for estimation of exposure effects from population-based disease rates and covariate data from risk factor surveys in each population group. A basic relative rate model specified for individuals is aggregated to produce a random effects relative rate model for the disease rates. Relative rate parameter estimates from aggregate data studies target the same parameters as individual-level studies but use between-group information in the data. We distinguish aggregate data studies from ecologic studies. Considerations in the design of aggregate studies are motivated by the need to gain clearer understanding of the role of diet in cancer aetiology. Simulation studies show that increasing the number of populations included in an aggregate data study from about 20 to 30-40 gives greater improvement in power than corresponding increases in the size of the survey sample in each population over an initial size of 100 individuals.

The authors used data from a population-based, case-control study of breast cancer conducted among women residing in King County, Washington State, who were 50-64 years of age in 1988-1990, to examine the relation of oral contraceptive use to the risk of breast cancer. There were no clear differences between cases and controls with respect to the total duration of oral contraceptive use, time since last use, or age at first or last use. While a small increase in risk was noted in women who had first used oral contraceptives within 20 years of the interview reference date, within that period there was no trend in risk observed with decreasing amounts of time since the last use of these agents. Overall, this study supports the absence of any strong association between oral contraceptive use and breast cancer risk during middle age in the cohort of women who first used these drugs.

We used data from a population-based case-control study to evaluate Janerich's hypothesis that reduced risk of breast cancer in women with multiple marriages may be attributable to an immune response to fetal or sperm antigens. Risk of breast cancer in women with multiple marriages was reduced relative to that in women who had been married only once; however, there was no indication that such risk was reduced among women whose full-term pregnancies were fathered by different men, relative to women whose pregnancies were each fathered by the same man. Increasing lifetime number of male sexual partners was associated with a trend of decreasing risk of breast cancer. Our results indicate that, if there are effects of exposure to fetal or male antigens on risk of female breast cancer, their impact may be heterogeneous.

Objective: To assess the risk of cervical neoplasia associated with the use of ovulation-inducing agents such as clomiphene citrate (CC) DESIGN: Case-cohort study., Setting: Infertility clinics in Seattle, Washington., Patients: A cohort of 3,837 women evaluated for infertility at some time during 1974-1985., Main Outcome Measure: Computer linkage with a population-based tumor registry was used to identify women diagnosed with cervical cancer before January 1, 1992. Data regarding infertility testing and treatment were abstracted from medical records for women who developed cancer and a randomly selected subcohort., Results: Thirty-six women in the cohort developed in situ or invasive cervical cancer in comparison with an expected number of 67.8 cases (standardized incidence ratio = 0.5, 95% confidence interval [CI] 0.4 to 0.7). Infertile women with fallopian tube abnormalities were at an increased risk of cervical cancer relative to women whose infertility was believed to be due to other causes. The risk among women who had taken CC was reduced relative to infertile women who had not used this drug (relative risk = 0.4, 95% CI 0.2 to 0.8). This association was present both in women with and without tubal abnormalities. However, the size of the reduction in risk was not influenced by duration of use., Conclusions: The hypothesis that use of antiestrogenic agents, such as CC, can lead to a reduced risk of cervical neoplasia warrants testing in other studies.

The purpose of this study was to assess: (1) the risk of breast cancer associated with use of ovulation-inducing agents (such as clomiphene citrate) as treatment for infertility; and (2) the risk associated with ovulatory abnormalities that result in infertility. We performed a case-cohort study among 3837 women evaluated for infertility at clinics in Seattle, Washington, at some time during 1974-1985. Computer linkage with a population-based tumor registry was used to identify women diagnosed with breast cancer before January 1, 1992. Data regarding infertility testing and treatment were abstracted from the infertility clinic medical records for women who developed breast cancer and a randomly selected subcohort. Twenty-seven women in the cohort developed in situ or invasive breast cancer, in comparison with an expected number of 28.8 cases (standardized incidence ratio, 0.9; 95% confidence interval (CI), ).6-1.4). Infertile women with evidence of an ovulatory abnormality were at a risk of breast cancer similar to that of women whose infertility was believed to be due to other causes. The risk among women who had taken clomiphene was reduced relative to infertile women who had not used this drug (adjusted relative risk, 0.5; 95% CI, 0.2-1.2), but the reduction in risk did not increase with duration of use. The possibility that use of clomiphene as treatment for infertility lowers the risk of breast cancer should be examined in other, larger studies.

We compared incidence rates of primary cancer of the thyroid among United States-born and foreign-born Chinese, Japanese, and Filipino residents of the US with rates among US-born Whites. Thyroid cancers diagnosed between 1973 and 1986 occurring among individuals 15 to 84 years of age residing in western Washington state, the San Francisco-Oakland (California) area, or the state of Hawaii were included in the analysis. Population estimates by age, gender, ethnicity, and country of birth were obtained for these areas from the US Bureau of the Census. Filipino women born in the Philippines had 3.2 (95 percent confidence interval = 2.7-3.8) times the rate of thyroid cancer of US-born White women, while US-born Filipino women were not at any increased risk. Philippine-born Filipino men also had a relatively high rate of thyroid cancer (relative risk [RR] = 2.6), more so than US-born Filipino men (RR = 1.5). Among Japanese, risk of thyroid cancer varied by birthplace, but the direction of the association differed by gender and by histologic type of cancer. No clear association with birthplace was noted among Chinese men or women. These data suggest that persons residing in one or more regions from which Filipino-Americans migrated have been exposed to environmental influences that have increased their subsequent risk of thyroid cancer.

Objective: To determine the risk of breast cancer in relation to the use of combined estrogen and progestin hormone replacement therapy (HRT)., Design: A population-based case-control study., Setting: The general female population of King County in western Washington State., Participants: Middle-aged (50 to 64 years) women, including 537 patients with incident primary breast cancer diagnosed between January 1, 1988, and June 30, 1990, who were ascertained through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry and 492 randomly selected control women without a history of breast cancer., Main Outcome Measure: Breast cancer risk in relation to use of menopausal hormones., Results: Menopausal hormones of some type had been used by 57.6% of breast cancer cases and 61.0% of comparison women. The women who had ever taken combined estrogen-progestin HRT, representing 21.5% of cases and 21.3% of controls, were not at increased risk of breast cancer (relative odds [RO] = 0.9; 95% confidence interval [CI], 0.7 to 1.3). Compared with nonusers of menopausal hormones, those who used estrogen-progestin HRT for 8 or more years had, if anything, a reduced risk of breast cancer (RO = 0.4; 95% CI, 0.2 to 1.0)., Conclusions: On the whole, the use of estrogen with progestin HRT does not appear to be associated with an increased risk of breast cancer in middle-aged women. Nonetheless, since the use of combined estrogen-progestin HRT has only recently become prevalent, future investigations must assess whether breast cancer incidence is altered many years after estrogen-progestin HRT has been initiated, particularly among long-term users.

We assessed the risk of cutaneous malignant melanoma associated with the presence of ovulatory abnormalities and with the use of ovulation-inducing agents (such as clomiphene citrate) in a cohort of 3,837 women evaluated at infertility clinics in Seattle, WA, between 1974 and 1985. Computer linkage with a population-based tumour registry was used to identify women diagnosed with melanoma before 1992. Data regarding infertility testing and treatment were abstracted from the infertility clinic medical records for women who developed cancer and a randomly selected subcohort. Twelve women in the cohort developed cutaneous malignant melanoma, in comparison with an expected number of 6.8 cases (standardized incidence ratio = 1.8; 95% confidence interval (CI) 0.9-3.1). Within the cohort, risk was increased among women who had used clomiphene during 12 or more menstrual cycles (relative risk = 2.2; 95% CI 0.5-10.2). All four of the women with this duration of clomiphene use who developed melanoma had ovulatory abnormalities, and three had also used human chorionic gonadotropin (HCG). No elevation in risk associated with the presence of ovulatory abnormalities was observed in the absence of at least 12 cycles of clomiphene exposure; also, there was no increased risk associated with long-term use of clomiphene among women without ovulatory abnormalities, but the number of such women was very small. Thus, it is not certain to what extent the observed increased risk of melanoma in this cohort (if not due to chance) may be attributable to the use of clomiphene or HCG, or is a reflection of some underlying hormonal abnormality for which the drug was administered.

The authors analyzed data from a population-based case-control study of breast cancer in middle-aged women residing in King County, Washington, to examine the relation between occupation and breast cancer risk. A total of 537 cases and 492 controls completed in-person interviews. Subjects provided job titles and years of employment for their three main occupations since age 18. While there were case-control differences in the frequency with which certain jobs were reported, all were within the limits of chance, given no true association. Also, few additional increases in risk were associated with long-term employment. Relative risk (RR) estimates were elevated for women working in precision textile and apparel jobs (six cases and one control, RR = 5.2). To a lesser extent, RR estimates were also elevated for receptionists, cosmetologists, and the category of painters/sculptors/printmakers. A slight increase in risk was associated with several occupations, including nursing and teaching.

Background: We assessed the risk of tubal pregnancy among women who (1) were currently using an intrauterine device (IUD) and (2) had discontinued IUD use while still sexually active and at risk of pregnancy using data from a multicentre case-control study of married women conducted in Indonesia., Methods: Cases were 560 women diagnosed with histologically confirmed ectopic pregnancy from April 1989 to August 1990 at any one of 11 participating hospitals. Controls were 1120 non-pregnant women similar in age and place of residence to the cases. In-person interviews were conducted to collect information regarding current and past contraceptive use as well as other demographic and personal characteristics., Results: Women currently using an IUD were considerably less likely than women not currently using contraception, but more likely than users of hormonal or surgical means of contraception, to develop a tubal pregnancy. Women who had discontinued using an IUD had a 70% subsequent increase in risk of tubal pregnancy (adjusted RR = 1.7, 95% Cl: 1.1-2.5) relative to women who had never used an IUD. This increase in risk was most pronounced in women who reported multiple episodes of IUD use and, to a lesser extent, in women with a long (> 3 year) duration of IUD use., Conclusions: The associations we observed are similar to those previously reported in studies conducted in developed countries. The results are of particular interest because this study was conducted in a location in which the Dalkon Shield IUD was never available, and among a population of married, gravid women for whom IUD use is generally considered most appropriate.

Background: Case reports and the results of a recent case-control study have raised questions about the potential neoplastic effects of medications used as treatment for infertility., Methods: We examined the risk of ovarian tumors in a cohort of 3837 women evaluated for infertility between 1974 and 1985 in Seattle. Computer linkage with a population-based tumor registry was used to identify women in whom tumors were diagnosed before January 1, 1992. Data on infertility testing and treatment were abstracted from the medical records of women who had ovarian cancer and those of a randomly selected comparison group. The risk of ovarian tumors associated with exposure to ovulation-inducing medications was assessed through an age-standardized comparison with the rate of ovarian tumors in the general population, and Cox regression analysis was used to compare the risk of cancer among women who received these medications with the risk among infertile women who did not receive them., Results: There were 11 invasive or borderline malignant ovarian tumors, as compared with an expected number of 4.4 (standardized incidence ratio, 2.5; 95 percent confidence interval, 1.3 to 4.5). Nine of the women in whom ovarian tumors developed had taken clomiphene; the adjusted relative risk among these women, as compared with that among infertile women who had not taken this drug, was 2.3 (95 percent confidence interval, 0.5 to 11.4). Five of the nine women had taken the drug during 12 or more monthly cycles. This period of treatment was associated with an increased risk of ovarian tumors among both women with ovarian abnormalities and those without apparent abnormalities (relative risk, 11.1; 95 percent confidence interval, 1.5 to 82.3), whereas treatment with the drug for less than one year was not associated with an increased risk., Conclusions: Prolonged use of clomiphene may increase the risk of a borderline or invasive ovarian tumor.

Using data from a population-based, case-control study, we assessed risk of tubal pregnancy associated with use of an intrauterine device (IUD) at the time of conception. Cases were 249 members of Group Health Cooperative of Puget Sound who experienced a tubal pregnancy between 1981 and 1986. Controls were 831 members at risk of ectopic pregnancy who were similar to cases with respect to age and county of residence, but otherwise selected at random. Risk of tubal pregnancy associated with current IUD use was compared separately to that among users of various other (or no) contraceptive methods. Tubal pregnancy was more likely to occur among IUD users than among women using oral contraceptives [relative risk (RR) = 3.8, 95% confidence interval (CI) = 1.5-9.9] or barrier methods (RR = 3.6, 95% CI = 1.6-8.1), or, to a lesser extent, among women who had been surgically sterilized (RR = 1.6, 95% CI = 0.8-3.5). In contrast, IUD users were much less likely to experience a tubal pregnancy (RR = 0.2, 95% CI = 0.1-0.4) than were women who were currently not contracepting. For most women, the decision to use an IUD occurs within the context of choosing among various contraceptive methods. Our results indicate that, for these women, the decision to use an IUD results in increased risk of ectopic pregnancy while the device is in use.

We assessed risk of tubal pregnancy associated with past use of an intrauterine device (IUD). Cases were 256 members of Group Health Cooperative of Puget Sound who experienced a tubal pregnancy between 1981 and 1986. Controls were 666 female members of the Cooperative at risk of ectopic pregnancy who were similar to cases with respect to age and county of residence, but otherwise selected at random. The presence of antibody to Chlamydia trachomatis was assessed in a sample of 134 cases and 182 controls. Women who had previously used an IUD for 3 or more years were more than twice as likely as women who had never used an IUD to have a tubal pregnancy (adjusted relative risk = 2.5, 95% confidence interval = 1.5-4.3). Among these long-term users of an IUD, risk of tubal pregnancy remained elevated for many years after the device was removed. Also, among long-term users, women known to have more than one IUD insertion were no more likely than women with one known insertion to develop a tubal pregnancy. When we restricted our analyses to women who used only copper-containing devices, the results were nearly identical. We conclude that extended past use of an IUD, including use of a copper device, increases the risk of tubal pregnancy.