A population-based study of contralateral breast cancer following a first primary breast cancer (Washington, United States)

To evaluate predictors of contralateral breast cancer risk, we examined data from a nested case-control study of second primary cancers among a cohort of women in western Washington (United States) diagnosed with breast cancer during 1978 through 1990 and identified through a population-based cancer registry. Cases included all women in the cohort who subsequently developed contralateral breast cancer at least six months after the initial diagnosis, but prior to 1992 (n=234). Controls were sampled randomly from the cohort, matched to cases on age, stage, and year of initial breast cancer diagnosis. Information on potential risk factors for second primary cancer was obtained through medical record abstractions and physician questionnaires. Women who were postmenopausal due to a bilateral oophorectomy (i.e., a surgical menopause) at initial breast cancer diagnosis had a reduction in contralateral breast cancer risk compared with premenopausal women (matched odds ratio [mOR]=0.25, 95 percent confidence interval [CI]=0.09–0.68), whereas no reduction in risk was noted among postmenopausal women who had had a natural menopause (mOR=0.90, CI=0.39–2.09). Among postmenopausal women, there was a suggestion of a lower risk associated with relatively high parity (2+). A family history of breast cancer was associated with an increased risk (mOR=1.96, CI=1.22–5.15) and varied little by menopausal status. Having an initial tumor with a lobular component (c.f. a ductal histology) was not related strongly to risk (mOR=1.47, CI=0.79–2.74). The results of the present and earlier studies argue that we have limited ability to predict the occurrence of a contralateral breast tumor. Better predictors will be required before diagnostic and preventive interventions can be targeted to subgroups of patients with unilateral breast cancer.Authors are with the Department of Epidemiology, University of Washington, Seattle, WA, USA (Drs Cook, White, Schwartz, Daling, Weiss); with the Fred Hutchinson Cancer Research Center, Seattle, WA (Drs Cook, White, Schwartz, McKnight, Daling, Weiss); and the Department of Biostatistics, University of Washington, Seattle, WA (Dr McKnight). Address correspondence to Dr Cook, MP-381, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104, USA. This research was supported in part by grants from the US National Cancer Institute (R35 CA 39779), the Agency for Health Care Policy and Research (1 RO3 HS08004-01), and by the Cancer Surveillance System of the Fred Hutchinson Cancer Research Center, which is funded by Contract No. N01-CN-05230 from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute with additional support from the Fred Hutchinson Cancer Research Center.     

Cutaneous melanoma following cervical intra-epithelial neoplasia in western washington state

Stimulated by a recent report from a Norwegian pathology institute of an excess risk of melanoma among women with cervical neoplasia, we analyzed the relevant data from a population-based cancer registry serving western Washington State (United States). Among 11,693 women diagnosed with cervicalintra-epithelial neoplasia (CIN) between 1974 and 1989 who were followed-up for at least a year, 14 cases of cutaneous melanoma were identified, in comparison with 13.7 cases expected (relative risk=1.0,95 percent confidence interval=0.5-1.7) based on the rates of melanoma among all women who resided in this area. While these results are at odds with those recently reported from the pathology institute, they are similar to those obtained in previous cancer-registry studies in several countries, which found little or no excess occurrence of melanoma following cervical cancer.Authors are with the Department of Epidemiology, University of Washington, Seattle, WA, USA. Drs Weiss and Schwartz are also with the Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Address correspondence to Dr Weiss, Department of Epidemiology, SC-36, University of Washington, Seattle, WA 98195, USA. This investigation was supported by PHS grant numbers 5T32 CA09168-17 and R35 CA39779 awarded by the US National Cancer Institute, DHHS.     

Noncontraceptive hormone use and risk of breast cancer

All British Columbia (Canada) women under 75 years of age who were diagnosed with breast cancer during 1988–89 were asked to complete a postal questionnaire which included detailed information on menopausal estrogen use. Controls were drawn from the Provincial Voters List, matched by five-year age category to the cases. The present analysis consists of 699 cases and 685 controls who were postmenopausal due to natural causes or to a hysterectomy. There was no overall increase in risk of breast cancer associated with ever-use of unopposed estrogen (odds ratio [OR] = 1.0,95 percent confidence interval [CI] = 0.8–1.3). For estrogen use of 10 years or longer, the relative risk [RR] was 1.6 (CI = 1.1–2.5). The risk estimate for current users was somewhat elevated (OR = 1.4, CI = 1.0–2.0). Compared with women who never used hormone preparations, women who had used estrogen plus progestogen had an RR of 1.2 (CI = 0.6–2.2). Our results suggest that ever-use of estrogen, with or without progestogen, does not appreciably increase the risk of breast cancer. However, long-term and recent use of unopposed estrogen may be associated with a moderately increased risk.Drs Yang and Band, and Mr Gallagher are with the British Columbia Cancer Agency, Vancouver, Britsh Columbia, Canada. Authors are also affiliated with the School of Public Health and Community Medicine, University of Washington, Seattle, WA, USA (Drs Yang, Daling, White, and Weiss), and the Fred Hutchinson Cancer Research Center, Seattle, WA, USA (Drs Daling, White, and Weiss). Address correspondence to Mr Gallagher, Division of Epidemiology, Biometry and Occupational Oncology, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC, Canada, V5Z 4E6. This project is funded partially by Health and Welfare Canada, Grant #6610-1834-55 and by Workers Compensation Board of BC.     

Endometrial cancer risk in estrogen users after switching to estrogen–progestin therapy

Objective It is unknown whether postmenopausal unopposed estrogen users are better off, in terms of endometrial cancer risk, switching to a combined estrogen–progestin regimen or stopping hormone use altogether. Methods We analyzed data from a series of three population-based case–control studies in western Washington state during 1985–1999, comparing proportions of “switchers” and “stoppers” in cases and controls. We also assessed whether the risk of endometrial cancer in either group of former unopposed estrogen users returned to that of never users. Results After multivariate adjustment using unconditional logistic regression, women who switched to a combined regimen with a progestin added for at least ten days/month (37 cases, 47 controls) had half the risk of endometrial cancer of women who stopped hormone use altogether (86 cases, 78 controls) (adjusted odds ratio = 0.5, 95% confidence interval: 0.3–1.1). Most subgroups of former users, whether they switched or stopped, had some increased risk of endometrial cancer compared to never users. Conclusions Results from this study suggest that unopposed estrogen users may reduce their risk of endometrial cancer more by switching to a combined regimen with progestin added for at least ten days/month than by stopping hormone use altogether.     

Non-contraceptive exogenous estrogens and risk of breast cancer: A review

Summary Results from epidemiologic and related studies of non-contraceptive estrogens and breast cancer are reviewed. Exogenous estrogens in high doses can enhance the risk of breast cancer. Moderate use of estrogens for menopausal symptoms probably has little effect on risk, but long-term users, and women who take high-strength preparations, appear to be at slightly increased risk. Exogenous estrogens probably reduce the protective effect of premenopausal oophorectomy, and may preferentially enhance the risk of breast cancer in women with some types of benign breast disease, although data from some studies do not support these conclusions. There is no evidence that the influence on risk of breast cancer is different for synthetic and conjugated estrogens. Needs for reanalyses of data from existing studies, and for additional investigations, are summarized. Address for Reprints: David B. Thomas, M.D., Dr.P.H., Program in Epidemiology and Biostatistics, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104, USA.     

Recency,duration, and progestin content of oral contraceptives in relation to the incidence of endometrial cancer (Washington,USA)

Women who have used combined oral contraceptives (COC) have a reduced risk of endometrial cancer relative to that of women who have never used oral contraceptives, but it is unclear whether the size of the reduction is influenced by the progestin content of the preparation. We analyzed data from two population-based case-control studies of endometrial cancer to investigate this question. Among women aged 40 to 59 years who were residents of King or Pierce Counties, Washington (United States), incident cases who were diagnosed during 1975–77 or 1985–87 were identified. Personal interviews were conducted with 316 such women and their responses compared with those of 501 controls who were selected by household surveys or random-digit dialing. A reduced risk of endometrial cancer associated with COC use was present only among users of five or more years' duration, and even then only in women who were not long-term users of unopposed postmenopausal estrogens. Among these women, the relative risk (RR) of endometrial cancer did not differ according to the progestin potency of the COC used: it was equally low for women who had used a COC with low progestin content (RR=0.2, 95 percent confidence interval [CI]=0.1–0.8) as for women who had used a COC with high progestin content (RR=0.3, CI=0.1–0.9). Our results argue that, if the reduced risk of endometrial cancer in long-term users of COCs is due to the progestins contained in these preparations, that amount of progestin in most COCs exceeds the threshold amount needed to produce this beneficial effect.This project was supported by Grant 5R35CA39779 and Contract NO1-CN-05230 from the US National Cancer Institute.     

Hormone replacement therapy and endometrial cancer

Postmenopausal hormone replacement therapy (HRT) using unopposed estrogens significantly increases endometrial cancer risk and should not be used in non-hysterectomized women. Even low-potency estrogens (oral estriol) or low-dose unopposed estrogens significantly enhance the risk to develop endometrial cancer. This risk is markedly reduced, when in addition to estrogens, progestins are administered for at least 10 days (better 14 days) per month. In some studies, a normalization of endometrial cancer risk to that of women receiving no HRT was only found when a continuous combined estrogen/progestin replacement was used. The use of progestins for less than 10 days per month and long-cycle regimens, where a progestin is added only every 3 months cannot be recommended. For women needing HRT, estrogen dose should be selected as low as possible and reassessment of the need of HRT should be performed annually.     

Epidemiology of the M-component immunoglobulin types of multiple myeloma

The purpose of this population-based case-control study was to learn whether risk factors differ for the individual immunoglobulin types of multiple myeloma. In particular, we sought to determine whether IgA and IgG myeloma were related to a history of exposure to reported IgA- and IgG-stimulating conditions, respectively, or to a history of selected occupational and physicochemical exposures. The M-component immunoglobulin type was determined from immunoelectrophoresis as reported in medical records, and exposure status was obtained through in-person interviews. IgG (56 percent) and IgA (22 percent) M-components predominated. For 17 percent of cases, no peak was found on immunoelectrophoresis; they were presumed to have light-chain myeloma. Persons with these three types of myeloma did not differ with respect to distributions of age or race, but a somewhat higher proportion of light-chain cases were women (58 percent cf 45 percent of all other cases). Detailed analysis of the IgA and IgG subtypes provided little evidence that they differ with respect to prior immune stimulation or employment in several specific jobs. IgA myeloma, but not IgG myeloma, was associated modestly with a history of exposure to chest and dental X-rays. Our study provides little evidence that IgA and IgG myeloma differ with respect to the risk factors examined.Ms Herrinton and Drs Koepsell, Weiss, and Daling are with the Department of Epidemiology, University of Washington, Seattle, WA, USA, and the Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Dr Demers is with the Department of Environmental Health, University of Washington, Seattle, WA, USA. Dr Taylor is with Group Health Cooperative of Puget Sound, Seattle, WA, USA. Dr Lyon is with the School of Medicine, University of Utah, Salt Lake City, UT, USA. Dr Swanson is with the Cancer Center, Michigan State University, East Lansing, MI, USA. Dr Greenberg is with the School of Public Health, Emory University, Atlanta, GA, USA. Address correspondence to Ms Lisa Herrinton, Fred Hutchinson Cancer Research Center, 1124 Columbia MP-381, Seattle, WA 98104, USA. The project was supported by grants CA23350, CA39779, and CA09168 from the US National Cancer Institute.     

Is estrogen plus progestin menopausal hormone therapy safe with respect to endometrial cancer risk?

Given the strong link between use of unopposed estrogens and development of endometrial cancers, estrogens are usually prescribed with a progestin, particularly for women with intact uteri. Some studies suggest that sequential use of progestins may increase risk; however, the moderating effects of usage patterns or patient characteristics, including body mass index (BMI), are unknown. We evaluated menopausal hormone use and incident endometrial cancer (n = 885) in 68,419 postmenopausal women with intact uteri enrolled in the National Institutes of Health‐American Association of Retired Persons Diet and Health study. Participants completed a risk factor questionnaire in 1996–1997 and were followed up through 2006. Hazard rate ratios (RRs) and 95% confidence intervals (CIs) were estimated using Cox regression. Among 19,131 women reporting exclusive estrogen plus progestin use, 176 developed endometrial cancer (RR = 0.88; 95% CI = 0.74–1.06). Long‐duration (≥10 years) sequential (<15 days progestin per month) estrogen plus progestin use was positively associated with risk (RR = 1.88; 95% CI = 1.36–2.60], whereas continuous (>25 days progestin per month) estrogen plus progestin use was associated with a decreased risk (RR = 0.64; 95% CI = 0.49–0.83). Increased risk for sequential estrogen plus progestin was seen only among thin‐to‐normal weight women (BMI < 25 kg/m²; RR = 2.53). Our findings support that specific categories of estrogen plus progestin use increases endometrial cancer risk, specifically long durations of sequential progestins, whereas decreased endometrial cancer risk was observed for users of short‐duration continuous progestins. Risks were highest among thin‐to‐normal weight women, presumably reflecting their lower endogenous estrogen levels, suggesting that menopausal hormones and obesity increase endometrial cancer through common etiologic pathways.     

Determinants of survival following the diagnosis of esophageal adenocarcinoma (United States)

The rapidly rising incidence of esophageal adenocarcinomas in the United States and western Europe remains unexplained. Most persons who develop the disease have had long-standing gastroesophageal reflux symptoms with concomitant Barrett's metaplasia. They are, therefore, potentially identifiable for endoscopic screening and cancer surveillance, which should facilitate the early detection of these tumors. We undertook these analyses to determine the extent to which the opportunity for early diagnosis and treatment of esophageal adenocarcinomas has been realized in the US. Specifically, using data from the Surveillance, Epidemiology, and End Results (SEER) program of the US National Cancer Institute, we examined changes in stage of disease at diagnosis and in survival between 1973 and 1991 and investigated patient characteristics as predictors of survival. Improvements in stage at diagnosis and in survival between 1973 and 1991 were minor and clinically insignificant; overall five-year survival never exceeded 10 percent. Stage of disease at diagnosis was the strongest determinant of subsequent survival; five-year survival with patients with in situ tumors was 68.2 percent. This survival advantage persisted up to 15 years after diagnosis and was independent of other prognostic factors. We conclude that the opportunity for reduction in esophageal cancer mortality has been largely unrealized in the US. In light of the increasing incidence of esophageal adenocarcinoma, efforts should be devoted to identifying those at highest risk of developing Barrett's metaplasia and subsequent adenocarcinoma, and to developing cost-effective primary prevention and cancer surveillance methods targetting them.Drs Farrow and Vaughan are with the Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, and the Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA, USA. Address correspondence to Dr Farrow at the Program in Epidemiology, Fred Hutchinson Cancer Research Center, 1124 Columbia St., MP-474, Seattle, WA 98104, USA. This work was supported by US NIH grants U01CA57949 and R01CA61202.     

Recent oral contraceptive use and risk of breast cancer (United States)

We examined the association between recent oral contraceptive (OC) use and the risk of breast cancer in data from a large population-based case-control study in the United States. Cases (n=6,751) were women less than 75 years old who had breast cancer identified from statewide tumor registries in Wisconsin, Massachusetts, Maine, and New Hampshire. Controls (n=9,311) were selected randomly from lists of licensed drivers (if aged under 65 years) and from lists of Medicare beneficiaries (if aged 65 through 74 years). Information on OC use, reproductive experiences, and family and medical history was obtained by telephone interview. After adjustment for parity, age at first delivery, and other risk factors, women who had ever used OCs were at similar risk of breast cancer as never-users (relative risk [RR]=1.1, 95 percent confidence interval [CI]=10–1.2). Total duration of usealso was not related to risk. There was a suggestion that more recent use was associated with an increased risk of breast cancer; use less than two years ago was associated with an RR of 1.3 (CI=0.9–1.9). However, only among women aged 35 to 45 years at diagnosis was the increase in risk among recent users statistically significantly elevated (RR=2.0, CI=1.1–3.9). Use prior to the first pregnancy or among nulliparous women was not associated with increased risk. Among recent users of OCs, the risk associated with use was greatest among non-obese women, e.g., among women with body mass index (kg/m²) less than 20.4, RR=1.7, CI=1.1–2.8. While these results suggest that, in general, breast cancer risk is not increased substantially among women who have used OCs, they also are consistent with a slight increased risk among subgroups of recent users.Authors are with the University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA (Dr Newcomb, Ms Trentham Dietz); NIEHS Epidemiology Branch, Research Triangle Park, NC (Dr Longnecker); Fred Hutchinson Cancer Research Center, Seattle, WA (Dr Surer); Department of Obstetrics and Gynecology, Pritzker School of Medicine, The University of Chicago, Chicago, IL (Dr Mittendorf); Department of Community and Family Medicine, Dartmouth Medical School, Hanover, NH (Dr Baron); Boston University, School of Public Health, Boston, MA (Dr Clapp); Department of Epidemiology and Department of Nutrition, Harvard School of Public Health, and Channing Laboratory, Harvard Medical School and Department of Medicine, Brigham and Women's Hospital, Boston, MA (Dr Willett). Address correspondence to: Dr Polly A. Newcomb, University of Wisconsin-Madison Comprehensive Cancer Center, 1300 University Ave., #4780, Madison, WI 53706, USA. Supported by Public Health Service (National Cancer Institute) grants R01 CA 47147 and R01 CA 47305.     

Colorectal cancer and solar radiation

It has been suggested that sunlight might have a role in the prevention of colorectal cancer via a mechanism involving vitamin D. We used data from nine population-based cancer registries in the United States to analyze incidence rates for colon and rectal cancer during 1973–84 as a function of regional variation in the levels of available solar radiation. Data were restricted to include only those persons born and diagnosed in the same state. Incidence rates of colon and rectal cancer among men tended to increase with decreasing levels of solar radiation. Compared to rates in New Mexico and Utah, for example, rates in the Detroit area (MI), Connecticut, and western Washington were 50 percent to 80 percent higher. Among women, colon cancer rates showed a similar trend, though of smaller magnitude; rates of rectal cancer among women did not vary in relation to levels of available solar radiation.Dr Emerson, at the time of this research, was with Dr Weiss at the Department of Epidemiology, University of Washington, School of Public Health and Community Medicine, Seattle, WA and the Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Address correspondence to Dr Emerson at her current address: Arizona Cancer Center, Room 2942, University of Arizona, Tucson, AZ 85724, USA. This research was supported in part by Grant No. 1-R35-CA39779 and Grant No. 5-T32-CA09168-13 from the National Cancer Institute.     

A population‐based cohort study on the use of hormone treatment and endometrial cancer in southern Sweden

Our aim was to determine the risk of endometrial cancer associated with long‐term use of combined hormone therapy (HT) and low‐potency estrogens. In this prospective population‐based cohort, 40,000 women aged 25–64 years, without prior cancer or hysterectomy, were included. The women answered 2 questionnaires at a 10‐year interval regarding HT use and personal details. Women were followed up for an average of 15.5 years through the National Cancer and Causes of Death Registry, representing 236,611 women years. Among the 17,822 postmenopausal women included, 166 cases of endometrial cancer were diagnosed. Only use of combined HT was related to a decreased risk of endometrial cancer (OR 0.3, 95% CI 0.1–0.8), the protective effect was found after 2 years, and increased with extended duration of use. “Only use” of low‐potency estrogens increased the risk of endometrial cancer almost to the same extent as use of high‐potency estrogens (OR 2.0, 95% CI 1.1–3.6 vs. OR 2.5, 95% CI 1.3–4.8), the increased risk was confined to non‐obese women in both groups. The risk was significantly increased for oral but not for local low‐potency estrogen users (OR 2.1, 95% CI 1.1–3.6 vs. OR 1.5, 95% CI 0.4–6.2, respectively). In long‐term estrogen users the risk was highest during the first 2 years, dropping slightly thereafter. Since low‐potency estrogen use increases the risk of endometrial cancer almost as much as high‐potency estrogen use, they should only be given if medically indicated. © 2009 UICC     

Depot-medroxyprogesterone acetate (dmpa) and risk of edometrial cancer

This is a report of results from a case-control study of the relationship of the long-acting progestational contraceptive, depot-medroxyprogesterone acetate (DMPA) to risk of endometrial carcinoma. Prior use of DMPA and information on known and suspected risk factors for endometrial cancer were ascertained in personal interviews with 122 women with histologically confirmed disease and 939 controls selected from 2 hospitals in Bangkok and 1 in Chiang Mai, Thailand. Based on 3 exposed cases and 84 exposed controls, the relative risk of endometrial cancer was estimated to be 0.21 (95% confidence interval = 0.06,0.79) in women who had ever used DMPA (but who had not first used DMPA in the year prior to diagnosis). All 3 exposed cases had also received estrogens pre-menopausally. Exposure to such estrogens enhanced risk of endometrial cancer and reduced the apparent protective effect of DMPA. Although based on small numbers of exposed women, the protective effect of DMPA appeared to last for at least 8 years after cessation of use. The reduction in risk of endometrial cancer is at least as great for DMPA as for combined oral contraceptives.     

The dose-effect relationship between 'unopposed' oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk

The 'unopposed oestrogen hypothesis' for endometrial cancer maintains that risk is increased by exposure to endogenous or exogenous oestrogen that is not opposed simultaneously by a progestagen, and that this increased risk is due to the induced mitotic activity of the endometrial cells. Investigation of the mitotic rate during the menstrual cycle shows that increases in plasma oestrogen concentration above the relatively low levels of the early follicular phase do not produce any further increase in the mitotic rate of endometrial cells. A modification of the unopposed oestrogen hypothesis which includes this upper limit in the response of endometrial cells to oestrogen is consistent with the known dose-effect relationships between endometrial cancer risk and both oestrogen replacement therapy and postmenopausal obesity; it also suggests that the mechanism by which obesity increases risk in premenopausal women involves progesterone deficiency rather than oestrogen excess, and that the protective effect of cigarette smoking may be greater in postmenopausal than in premenopausal women. Detailed analysis of the age-incidence curve for endometrial cancer in the light of this hypothesis suggests that there will be lifelong effects of even short duration use of exogenous hormones. In particular, 5 years of combination-type oral contraceptive use is likely to reduce a woman's lifetime risk of endometrial cancer by some 60%; whereas 5 years of unopposed oestrogen replacement therapy is likely to increase her subsequent lifetime risk by at least 90%; and even 5 years of 'adequately' opposed therapy is likely to increase subsequent lifetime risk by at least 50%.     

Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy—long-term follow-up of a Swedish cohort

We analyzed cancer incidence and mortality in a cohort of 22,597 Swedish women who were prescribed replacement hormones. After 13 years of follow-up in national registries, 2,330 incident cancer cases and 848 cancer deaths were observed. Overall, our results were reassuring since incidence rate ratios (SIRs) for 16 cancer sites and mortality ratios (SMRs) for all 10 examined sites were at, or lower than, unity. However, we found that exposure to an estrogen-progestin combined brand was associated with an increasing relative risk of breast cancer with follow-up time, the SIR reaching 1.4 (95% CI 1.1–1.8) after 10 years of follow-up. The relative risk of endometrial cancer was substantially increased, with the highest SIR of 5.0 (95% CI 1.6–5.9) in women prescribed estrogens alone, whereas those given an estrogen-progestin combination showed no elevation in risk. The risk estimates for liver and biliary tract cancers and for colon cancer were reduced by about 40%, notably in women prescribed the estradiol-progestin compound. Further detailed analyses revealed no evidence of adverse or protective effects on the risk of ovarian, uterine cervical, vulvar/vaginal, rectal, pancreatic, renal, lung, thyroid and other endocrine cancers, brain tumors, malignant melanoma or other skin cancers. Hormone replacement therapy was not associated with an increase in mortality for any cancer site, at this time of follow-up. For breast and endometrial cancers, SMRs were below baseline but tended to increase with follow-up time. We conclude that hormone replacement increases the endometrial-cancer risk after unopposed estrogens and the breast-cancer risk—notably after estrogen-progestin combined therapy—and tentatively suggest that it exerts a protective effect against colon and liver cancer risks. © 1996 Wiley-Liss, Inc.     

Circulating levels of sex steroid hormones and risk of endometrial cancer in postmenopausal women

Experimental and epidemiological data support a role for sex steroid hormones in the pathogenesis of endometrial cancer. The associations of pre‐diagnostic blood concentrations of estradiol, estrone, testosterone, androstenedione, DHEAS and SHBG with endometrial cancer risk were investigated. A case‐control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). Cases were 124 postmenopausal women with invasive endometrial cancer. For each case, 2 controls were selected, matching the case on cohort, age and date of recruitment. Only postmenopausal women who did not use exogenous hormones at the time of blood donation were included. Odds ratios (OR) and their 95% confidence intervals (CI) were estimated by conditional logistic regression. ORs (95% CI) for endometrial cancer for quartiles with the highest hormone levels, relative to the lowest were as follows: 4.13 (1.76–9.72), p_trend = 0.0008 for estradiol, 3.67 (1.71–7.88), p_trend = 0.0007 for estrone, 2.15 (1.05–4.40), p_trend = 0.04 for androstenedione, 1.74 (0.88–3.46), p_trend = 0.06 for testosterone, 2.90 (1.42–5.90), p_trend = 0.002 for DHEAS and 0.46 (0.20–1.05), p_trend = 0.01 for SHBG after adjustment for body mass index, use of oral contraceptives and hormone replacement therapy. The results of our multicenter prospective study showed a strong direct association of circulating estrogens, androgens and an inverse association of SHBG levels with endometrial cancer in postmenopausal women. The effect of elevated androstenedione and testosterone levels on disease risk seems to be mediated mainly through their conversion to estrogens, although an independent effect of androgens on tumor growth cannot be ruled out, in particular in the years close to diagnosis. © 2003 Wiley‐Liss, Inc.     

Endometrial carcinoma risks among menopausal estrogen plus progestin and unopposed estrogen users in a cohort of postmenopausal women.

BACKGROUND: Because unopposed estrogen substantially increases endometrial carcinoma risk, estrogen plus progestin is one menopausal hormone therapy formulation for women who have not had a hysterectomy. However, endometrial carcinoma risks among estrogen plus progestin users and among former unopposed estrogen users are not firmly established. METHODS: We evaluated endometrial carcinoma risks associated with estrogen plus progestin and unopposed estrogen therapies in 30,379 postmenopausal Breast Cancer Detection Demonstration Project follow-up study participants. We ascertained hormone therapy use and other risk factors during telephone interviews and mailed questionnaires between 1979 and 1998. We identified 541 endometrial carcinomas via self-report, medical records, the National Death Index, and state cancer registries. Poisson regression generated time-dependent rate ratios (RR) and 95% confidence intervals (95% CI). RESULTS: Endometrial carcinoma was significantly associated with estrogen plus progestin only use (n = 68 cancers; RR, 2.6; 95% CI, 1.9-3.5), including both sequential (progestin <15 days per cycle; n = 32 cancers; RR, 3.0; 95% CI, 2.0-4.6) and continuous (progestin at least 15 days per cycle; n = 15 cancers; RR, 2.3; 95% CI, 1.3-4.0) regimens. The RR increased by 0.38 (95% CI, 0.20-0.64) per year of estrogen plus progestin use, and RRs increased with increasing duration of use for both regimens. The strong association with unopposed estrogen use declined after cessation but remained significantly elevated > or =10 years after last use (RR, 1.5; 95% CI, 1.0-2.1). CONCLUSIONS: Both estrogen plus progestin regimens significantly increased endometrial carcinoma risk in this study. Risks among unopposed estrogen users remained elevated long after last use. The prospect that all estrogen plus progestin regimens increase endometrial carcinoma risk deserves continued research.     

Risk of endometrial cancer following estrogen replacement with and without progestins.

BACKGROUND: Unopposed estrogen replacement therapy (i.e., estrogen without progestins) increases the risk of endometrial cancer. In this study, we examined the endometrial cancer risk associated with combined estrogen-progestin regimens currently in use, since the safety profiles of these regimens have not been clearly defined. METHODS: We conducted a nationwide population-based, case-control study in Sweden of postmenopausal women aged 50-74 years. We collected information on use of hormone replacement from 709 case patients with incident endometrial cancer and from 3368 control subjects. We used unconditional logistic regression to calculate odds ratios (ORs) as estimates of relative risks. All individual comparisons were made with women who never used the respective hormone replacement regimens. RESULTS: Treatment with estrogens alone was associated with a marked duration- and dose-dependent increase in the relative risk of endometrial cancer. Five or more years of treatment had an OR of 6.2 for estradiol (95% confidence interval [CI] = 3.1-12.6) and of 6.6 for conjugated estrogens (95% CI = 3.6-12.0). Following combined estrogen-progestin use, the association was considerably weaker than that for estrogen alone; the OR was 1.6 (95% CI = 1.1-2.4) after 5 or more years of use. This increase in risk was confined to women with cyclic use of progestins, i.e., fewer than 16 days per cycle (most commonly 10 days per cycle [OR = 2.9; 95% CI = 1.8-4.6 for 5 or more years of use]), whereas continuous progestin use along with estrogens was associated with a reduced risk (OR = 0.2; 95% CI = 0.1-0.8 for 5 or more years of use). CONCLUSION: The risk of developing endometrial cancer is increased after long-term use of estrogens without progestins and with cyclically added progestins. Continuously added progestins may be needed to minimize the endometrial cancer risk associated with estrogen replacement therapy.     

Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review.

Endometrial cancer is a disease of the affluent, developed world, where epidemiological studies have shown that > or =40% of its incidence can be attributed to excess body weight. An additional proportion may be because of lack of physical activity. Alterations in endogenous hormone metabolism may provide the main links between endometrial cancer risk, and excess body weight and physical inactivity. Epidemiological studies have shown increased endometrial cancer risks among pre- and postmenopausal women who have elevated plasma androstenedione and testosterone, and among postmenopausal women who have increased levels of estrone and estradiol. Furthermore, there is evidence that chronic hyperinsulinemia is a risk factor. These relationships can all be interpreted in the light of the "unopposed estrogen" hypothesis, which proposes that endometrial cancer may develop as a result of the mitogenic effects of estrogens, when these are insufficiently counterbalanced by progesterone. In our overall synthesis, we conclude that development of ovarian hyperandrogenism may be a central mechanism relating nutritional lifestyle factors to endometrial cancer risk. In premenopausal women, ovarian hyperandrogenism likely increases risk by inducing chronic anovulation and progesterone deficiency. After the menopause, when progesterone synthesis has ceased altogether, excess weight may continue increasing risk through elevated plasma levels of androgen precursors, increasing estrogen levels through the aromatization of the androgens in adipose tissue. The ovarian androgen excess may be because of an interaction between obesity-related, chronic hyperinsulinemia with genetic factors predisposing to the development of ovarian hyperandrogenism.