Cigarette smoking, alcohol consumption, and breast cancer risk.

The effects of cigarette smoking and alcohol consumption on breast cancer risk were investigated in 276 primary, histologically confirmed breast cancer patients and 1,519 community-based comparison subjects identified in 1977 and 1978 in North Carolina. Data on both behaviors and other pertinent personal and medical characteristics were obtained by interview. Analytic methods included stratification and logistic regression. Among current cigarette smokers of 1-20 cigarettes per day and over 20 per day, the odds ratios (ORs) adjusted for age, race, alcohol consumption, estrogen use, and oral contraceptive use for breast cancer were 0.75 [95% confidence interval (CI) 0.52-1.09] and 0.57 (95% CI 0.30-1.08), respectively. A decrease in risk was not seen in former smokers. With respect to alcohol consumption, the adjusted OR for those having one drink or more per week compared to those having less than one was 1.45 (95% CI 0.99-2.12). If the comparison was ever versus never drinkers, the adjusted OR was 1.47 (95% CI 1.10-1.97); for current drinkers versus nondrinkers, the adjusted OR was 1.89 (95% CI 1.40-2.56). The ORs were adjusted for age, race, cigarette smoking, estrogen use, an oral contraceptive use. These data supports those reports showing an inverse association of cigarette smoking and a positive association of alcohol consumption with breast cancer risk.

Internal sequence variations in the Ha-ras variable number tandem repeat rare and common alleles identified by minisatellite variant repeat polymerase chain reaction.

In this report, we describe the sequence allelotyping of the Ha-ras variable number tandem repeat (VNTR) region using a minisatellite variant repeat (MVR)-PCR approach. This method permits the rapid identification of internal sequence variations among the VNTR alleles, exploiting the presence of two polymorphic sites within the 28-bp repeat subunits that give rise to four distinct repeat types. Using MVR-PCR, 20 to 25 repeats at the 5' end of the VNTR can be sequenced rapidly and reliably. MVR typing of the common alleles a1, a2, a3, and a4 shows that the first six repeats at the 5' end of each allele constitutes an invariant region. Beginning with repeat 7, characteristic "signature" MVR patterns emerge for each common allele. The a1 and a2 common alleles were found to consist of specific repeat types 1, 2, and 3, whereas a3 and a4 contain an additional repeat type 4 not present in the smaller alleles. MVR typing of rare-length alleles indicates that they are comprised of disorganized sequences, although they usually bear a resemblance to one of the common alleles at the 5'-most end. These results suggest that the rare alleles may be generated from recombination or gene conversion-type events involving the common progenitor alleles. MVR typing could, therefore, improve the ascertainment of rare Ha-ras alleles and may provide molecular insights into the genesis of cancer-associated alleles.

HER-2/neu amplification in benign breast disease and the risk of subsequent breast cancer.

PURPOSE: The purpose of this study was to determine whether the presence of HER-2/neu gene amplification and/or overexpression in benign breast disease was associated with an increased risk of subsequent breast cancer. PATIENTS AND METHODS: We conducted a nested case-control study of a cohort of women who were diagnosed with benign breast disease at the Mayo Clinic and who were subsequently observed for the development of breast cancer. Patients who developed breast cancer formed the case group, and a matched sample from the remaining cohort served as controls. Benign tissue samples from 137 cases and 156 controls and malignant tissues from 99 cases provided DNA or tissue for evaluation of HER-2/neu amplification and protein overexpression. RESULTS: Among the controls, seven benign tissues (4.5%) demonstrated low-level HER-2/neu amplification, whereas 13 benign (9.5%) and 18 malignant (18%) tissue specimens from cases exhibited amplification. HER-2/neu amplification in benign breast biopsies was associated with an increased risk of breast cancer (odds ratio ¿OR = 2.2; 95% confidence interval ¿CI, 0.9 to 5.8); this association approached statistical significance. The risks for breast cancer associated with benign breast histopathologic diagnoses were OR = 1.1 (95% CI, 0.6 to 1.9) for lesions exhibiting proliferation without atypia and OR = 1.5 (95% CI, 0.4 to 5.6) for the diagnosis of atypical ductal hyperplasia. For women having both HER-2/neu amplification and a proliferative histopathologic diagnosis (either typical or atypical), the risk of breast cancer was more than seven-fold (OR = 7.2; 95% CI, 0.9 to 60.8). Overexpression of the HER-2/neu protein product, defined as membrane staining in 10% or more of epithelial cells, was found in 30% of the breast tumors but was not detected in any of the benign breast tissues. Case patients who had HER-2/neu gene amplification in their malignant tumor were more likely to have had HER-2/neu amplification in their prior benign biopsy (P =.06, Fisher's exact test). CONCLUSION: Women with benign breast biopsies demonstrating both HER-2/neu amplification and a proliferative histopathologic diagnosis may be at substantially increased risk for subsequent breast cancer.

Active and passive cigarette smoke exposure and cervical intraepithelial neoplasia.

This case-control analysis presents odds ratios for active and passive cigarette smoke exposure and cervical intraepithelial neoplasia of levels II and III (CIN II and CIN III) while controlling for confounders. From 1987 to 1988, 103 biopsy-conformed incident cases of CIN II or III and 268 controls with normal cervical cytology were enrolled. Seventy % of cases were cigarette smokers, while only 30% of controls had ever smoked. The adjusted odds ratio for current cigarette smoking was 3.4 (95% confidence interval, 1.7-7.0). The following confounders were included in logistic regression models: age, race, education, number of sex partners, contraceptive use, sexually transmitted disease history, and Pap smear history. The risk of CIN II/III increased with increasing years of cigarette smoking and with increasing pack-years of exposure. Smoking was associated more strongly with CIN III than CIN II. The effect of passive cigarette smoke exposure was explored separately for smokers and nonsmokers and was found not to be consistently associated with CIN II/III when controlling for confounders.

HRAS protooncogene polymorphism and breast cancer.

The potential association of polymorphism in the HRAS protooncogene variable repeat region with susceptibility to cancer has become a controversial topic. A number of studies have produced results that appear inconsistent. We report here a multidisciplinary study with a combined molecular and epidemiological approach, addressing the specific question of the association of rare HRAS alleles and breast cancer. Extensive questionnaire data and peripheral blood for DNA extraction were obtained from 160 cases of incident breast cancer and from two control groups totaling 405 unaffected women from five outpatient clinics in North Carolina between April 1990 and June 1991. Controls were frequency matched to cases on age and race. Our results, adjusted for race and age, showed a positive overall association between the presence of rare HRAS alleles and breast cancer. This relationship was somewhat stronger in control group 2 (odds ratio = 3.0; P < 0.01) than in control group 1 (odds ratio = 2.0; P < 0.05). The relationship was 3-6 times stronger in blacks than in whites. In the case series, rare HRAS alleles were associated with hormone receptor negative tumors. This association was stronger in blacks and younger women. There was no confounding or effect modification by any other breast cancer risk factors. We conclude that rare HRAS alleles are associated with breast cancer and that this association may be stronger in black women than in white women. Rare HRAS alleles may also be related to more aggressive tumors, particularly in blacks and younger women. HRAS alleles have the potential to become a valuable screening biomarker for women at increased risk for breast cancer.

Risk of breast cancer according to the status of HER-2/neu oncogene amplification.

We examined risk factors for breast cancer after subdividing cases based on the presence of HER-2/neu oncogene amplification in their tumors. Data were from the Carolina Breast Cancer Study, a population-based, case-control study of 577 invasive breast cancer patients, diagnosed during 1993-1996 and ages 20-74 years, and 790 controls frequency-matched on race and age. Information on breast cancer risk factors was obtained from structured personal interviews. About 20% of paraffin-embedded tissues from the breast cancers of cases were identified as positive for HER-2/neu amplification (HER-2/neu+) by differential PCR. Early age at menarche, higher waist:hip ratio, and family history of breast or ovarian cancer were associated with elevated odds ratios (ORs) for both HER-2/neu+ and HER-2/neu- breast cancers. Breastfeeding for at least 1 year was inversely associated with HER-2/neu+ breast cancer [OR, 0.3; 95% confidence interval (CI), 0.1-0.7] more so than HER-2/neu- breast cancer (OR, 0.8; 95% CI, 0.5-1.2). Most of the remaining risk factors had ORs around 1.0 for both HER-2/neu+ and HER-2/neu- breast cancers, although a few exhibited possible associations with one disease subtype in analyses stratified by menopausal status. These study results suggest that most recognized breast cancer risk factors do not operate through HER-2/neu amplification in breast carcinogenesis. Differential effects of long-term breastfeeding by HER-2/neu amplification status have been observed in earlier studies and are provocative; however, the direction and magnitude of the associations have not been consistent.

32P-postlabeling analysis of DNA adducts in human sperm cells from smokers and nonsmokers.

To determine the feasibility of using human sperm cells for DNA 32P-postlabeling analyses, and to evaluate the baseline level and the possible presence of smoking-related DNA adducts in these cells, sperm DNA was isolated from specimens obtained from 12 heavy smokers, 12 light smokers, and 12 nonsmokers. Background levels of radioactivity were minimized by using magnet transfer of 32P-labeled mononucleotides to new polyethyleneimine cellulose plates. Compared with placental tissues, few adducts were observed. Diffuse radioactivity observed in some of the autoradiograms was minimally above background but the level of radioactivity expressed as putative adducts/nucleotide was not related to smoking status. It was not clear, in some cases, whether this radioactivity was associated with chemically bound adducts or was from nonspecifically bound chemicals, radiolabeled enzymes, or other proteins. One major discrete DNA adduct of unknown chemical structure was detected in three of the 36 samples analyzed (one nonsmoker and two smokers). Based on the level of radioactivity associated with various dilutions of a benzo(a)pyrene-derived adduct, our limit of sensitivity was at least 1.2 adducts/10(9) nucleotides. Our study emphasizes the need to more clearly define the significance of background radioactivity associated with DNA adduct maps where the measured adduct levels approximate detection limits defined by visual observance of adduct spots. This point is particularly relevant given that the 32P-postlabeling procedures rely, in part, on visual verification of the presence of DNA adducts.

Nicotine and cotinine in the cervical mucus of smokers, passive smokers, and nonsmokers.

Although epidemiological studies suggest that cigarette smoking is a risk factor for cervical cancer, further evidence is required to document the biological plausibility of this relationship. This study obtained cervical mucus, using a cervical flush technique, from 50 patients in a neoplasia clinic. Nicotine was detected in the cervical mucus of all 25 smokers and cotinine in the mucus of 84% of the smokers; nicotine and cotinine levels were correlated (P < or = 0.10) with both the number of cigarettes usually smoked and the number smoked in the last 24 h. Nicotine and cotinine levels for passive smokers and nonexposed women were much lower than for women who currently smoked, with little difference found between the nonsmoking women who did and did not report passive smoke exposure. In the one woman who reported smokeless tobacco use, both nicotine and cotinine were detected at much higher levels than for other nonsmoking women. These results indicate that tobacco constituents do indeed reach the uterine cervix, suggesting that they could play a causal role in the development of cervical cancer.

Association between high-density lipoprotein cholesterol and breast cancer varies by menopausal status.

A nested case-control study was conducted to investigate the hypothesis that women with high levels of high-density lipoprotein cholesterol (HDL-C) are at an increased risk of breast cancer. The source population was a cohort of 95,000 women enrolled in the Kaiser Permanente Medical Care Program who underwent a routine multiphasic health examination between 1964 and 1971. From the more than 2,000 breast cancer cases diagnosed in this cohort, 200 cases were randomly selected for this study. For each case, one control who matched on age and date of examination was chosen. Lipid and lipoprotein levels were measured in archived serum samples collected at the time of the women's examinations. Breast cancer risk factor information was obtained from questionnaires completed by the women when their blood was drawn and was supplemented with information from medical records. HDL-C levels were not significantly different between the cases and controls overall; however, a statistically significant interaction between the HDL-C level and menopausal status at diagnosis was detected. Premenopausal cases had mean HDL-C levels 3.48 mg/dl lower than matched controls [95% confidence interval (CI), -7.05, 0.09], whereas postmenopausal cases had levels 2.05 mg/dl higher than controls (95% CI, -0.94, 5.03). In multivariate conditional logistic regression analyses, the odds ratio associated with each 1 mg/dl increase in HDL-C was 0.96 (95% Cl, 0.93-1.0) for premenopausal women and 1.02 (95% CI, 0.99-1.05) for postmenopausal women. Although many breast cancer risk factors are associated with high HDL-C, the relationship between breast cancer and HDL-C was independent of other factors evaluated.

Breast cancer survival and the timing of tumor removal during the menstrual cycle.

In a retrospective cohort study of 262 premenopausal breast cancer patients treated at the Mayo Clinic between 1965 and 1985, we investigated whether survival was associated with the timing of tumor removal during the menstrual cycle. Participants were women < or = 50 years old who had not used exogenous hormones, been pregnant, been lactating, or given birth within 6 months of diagnosis. The menstrual cycle day at surgery was used to assign women to group 1 (cycle days 0-7), group 2 (cycle days 8-15), or group 3 (after cycle day 15). Cox proportional hazards analysis adjusting for age at diagnosis, stage, tumor size, grade, and node involvement showed a nonsignificantly worse survival for group 2 than for group 3 [hazard ratio (HR), 1.41; 95% confidence interval (CI), 0.89-2.23]. Stratification revealed that the association between survival and timing of tumor removal during the menstrual cycle was slightly stronger among patients with stage II disease (adjusted HR, 1.56; 95% CI, 0.92-2.63). The association was the same among patients with stage II disease and node involvement (adjusted HR, 1.57; 95% CI, 0.82-3.03). Prospective studies using hormone measurements to define menstrual cycle status more accurately than the reported day of the menstrual cycle could provide further insight about the postulated association.

Vitamin D and prostate cancer: a prediagnostic study with stored sera.

This study evaluates the risk of prostate cancer in relation to serum levels of the major vitamin D metabolites, 25-hydroxyvitamin D (25-D3) and 1,25-dihydroxyvitamin D (1,25-D). Between 1964 and 1971, more than 250,000 serum samples were collected from members of the Kaiser Permanente Medical Care Plan in Oakland and San Francisco and stored for future use. Levels of 25-D and 1,25-D were measured in samples from 90 black and 91 white men diagnosed with prostate cancer before December 31, 1987 and controls individually matched on age, race, and day of serum storage. Mean serum 1,25-D was 1.81 pg/ml lower in cases than in matched controls (P = 0.002). Risk of prostate cancer decreased with higher levels of 1,25-D especially in men with low levels of 25-D. However, mean 25-D was not significantly different in cases and controls. The association of lower 1,25-D with prostate cancer was found in men above the median age of 57 years at serum storage but not younger men and was similar in black and white men. In men > or = 57 years of age, 1,25-D was an important predictor of risk for palpable and anaplastic tumors but not for tumors incidentally discovered during surgery to treat the symptoms of benign prostatic hyperplasia or well differentiated tumors.

Hormones and breast and endometrial cancers: preventive strategies and future research.

A number of hormonal approaches for prevention of endometrial and breast cancers have been proposed. Because of the hormonal responsiveness of both tumors, much attention has focused on effects of exogenous hormone use. Although estrogens in hormone replacement therapy increase the risk of endometrial cancer, the disease is substantially reduced by long-term use of oral contraceptives. The issues with breast cancer are more complex, mainly because of a variety of unresolved effects. Long-term estrogen use is associated with some increase in breast cancer risk, and certain patterns of oral contraceptives appear to predispose to early-onset disease. With respect to estrogens, preventive approaches for both tumors would include use for as limited periods of time as possible. Addition of a progestin appears to lower estrogen-associated endometrial disease, but its effect on breast cancer risk remains less clear. Additional studies on effects of detailed usage parameters should provide useful insights into etiologic mechanisms. Other preventive approaches for endometrial cancer that may work through hormonal mechanisms include staying thin, being physically active, and maintaining a vegetarian diet. Breast cancer risk may possibly be reduced by extended periods of breastfeeding, restriction of intake of alcoholic beverages, remaining thin later in life, and being physically active. Additional research is needed to clarify the biologic mechanisms of these associations. The bridging of epidemiology with the biologic sciences should clarify many unresolved issues and lead to better preventive approaches.

Human tissue monitoring and specimen banking: opportunities for exposure assessment, risk assessment, and epidemiologic research.

A symposium on Human Tissue Monitoring and Specimen Banking: Opportunities for Exposure Assessment, Risk Assessment, and Epidemiologic Research was held from 30 March to 1 April 1993 in Research Triangle Park, North Carolina. There were 117 registered participants from 18 states and 5 foreign countries. The first 2 days featured 21 invited speakers from the U.S. Environmental Protection Agency, the Centers for Disease Control and Prevention, the National Institute of Environmental Health Sciences, various other government agencies, and universities in the United States, Canada, Germany, and Norway. The speakers provided a state-of-the-art overview of human exposure assessment techniques (especially applications of biological markers) and their relevance to human tissue specimen banking. Issues relevant to large-scale specimen banking were discussed, including program design, sample design, data collection, tissue collection, and ethical ramifications. The final group of presentations concerned practical experiences of major specimen banking and human tissue monitoring programs in the United States and Europe. The symposium addressed the utility and research opportunities afforded by specimen banking programs for future research needs in the areas of human exposure assessment, risk assessment, and environmental epidemiology. The third day of the symposium consisted of a small workshop convened to discuss and develop recommendations to the U.S. Environmental Protection Agency regarding applications and utility of large-scale specimen banking, biological monitoring, and biological markers for risk assessment activities.

Oral contraceptive use and cervical intraepithelial neoplasia.

To explore the somewhat controversial relationship between oral contraceptives and pre-invasive cervical cancer, 103 cases of biopsy-confirmed cervical intraepithelial neoplasia (CIN) II or CIN III were compared with 258 controls who had normal cervical cytology. Cases were slightly less likely than controls to have ever used oral contraceptives; the odds ratio, controlling for age, socioeconomic status, barrier method use, smoking history, age at first sexual intercourse, number of sex partners, current marital status, and number of Pap smears, was 0.7 (95% CI 0.3-1.6). Recency, latency, duration, and age at first oral contraceptive use were evaluated and in no instance was oral contraceptive use positively associated with CIN. This study adds to the body of knowledge that oral contraceptives are not associated with pre-invasive cervical cancer. Further, if oral contraceptive users continue to be regularly screened, their risk of developing the more invasive lesions should be very low.

PIP: Between September 1987 and November 1988, 103 University of North Carolina Hospitals (UNCH) Dysplasia Clinic patients with newly diagnosed, biopsy-confirmed cervical intraepithelial neoplasia (CIN) II or CIN III were enrolled as cases. They were 18-45 years old, black or white, nonpregnant North Carolina residents. 40 cases were CIN II and 63 cases were CIN III confirmed histologically. The controls were 258 UNCH Family Practice Center patients with normal cervical cytology. All subjects participated in a 15-minute structured interview. The Hollingshead Index was used as a proxy for socioeconomic status (SES). Known risk factors for cervical neoplasia were found to be risk factors for CIN II and CIN III. Compared with controls, cases were younger (odds ratio [OR] = 3.4 for those under 25 years of age), less educated (OR - 13.3 for 13 years), and of lower SES. Cases were more likely to have been divorced (OR - 2.7), to be cigarette smokers (OR = 3.4), to have ever been pregnant (OR - 2.6), to have had more than 2 sex partners (OR = 5.0), to have reported having had a sexually transmitted disease (gonorrhea, chlamydia, herpes, venereal warts, or pelvic inflammatory disease) (OR = 2.9), and to have had at least 3 Pap smears in the 5 years prior to study recruitment (OR = 1.7). Cases were less likely to have used a barrier method of contraception (OR = 0.3). 80.6% of cases and 81.0% of controls had ever used oral contraceptives (OCs); thus, the crude OR was 1.0. Adjustment of the OR for all confounders (age, SES, ever-use of barrier methods, smoking history, age at 1st sexual intercourse, lifetime number of male sex partners, current marital status, and number of Pap smears) reduced the OR to 0.7 (95% confidence interval 0.3-1.6). Recency, latency, duration, and age at 1st OC use were compared without finding any positive association between OC use and CIN.

Risk factors for menopausal hot flashes.

OBJECTIVE: To find predictors of hot flashes at natural menopause. METHODS: A cross-sectional sample of 334 black and white, naturally menopausal women was selected from a control group in a population-based study of reproductive cancers in central North Carolina. Women reported whether they had experienced hot flashes at the time of menopause. Life-style factors and reproductive histories of those with and without hot flashes were compared. RESULTS: Compared to women who were older at menopause, those reporting natural menopause before age 52 years had a significantly increased probability of having hot flashes (prevalence ratio 1.5, P = .04). Less than a high school education was significantly related to an increased probability of hot flashes (prevalence ratio 1.4, P = .20). There was significant interaction between cigarette smoking and body mass index (BMI), so that thin women who smoked in the premenopausal period were most likely to experience hot flashes (prevalence ratio 1.9, P = .03). Among non-smokers, BMI appeared to have no effect on the probability of hot flashes. Alcohol use, although not statistically significant, suggested a positive relation with hot flashes over and above that incurred from smoking. In addition, menarche before the age of 12 (prevalence ratio 0.6, P = .08) and a history of irregular menstrual cycles (prevalence ratio 0.6, P = .08) were marginally related to a decreased prevalence of hot flashes. Race, parity, and age at first and last pregnancy had no relation to hot flashes. CONCLUSION: Socioeconomic factors and those related to the decline of estrogen production are related to the occurrence of hot flashes at the time of menopause.

Oral contraceptives and breast cancer: a case-control study with hospital and community controls.

Several recent reports have noted an increase risk of breast cancer associated with the use of oral contraceptives (OCs) among various subgroups of young women. These reports spurred us to analyze data from a case-control study in North Carolina of 158 breast cancer patients, 326 hospital controls, and 1140 community controls less than 60 years of age. A logistic regression model was used to calculate odds ratios and 95% confidence intervals and to control for potential confounders. No association between ever-use of OCs and the risk of breast cancer was found for cases compared with either control group. No increased risk was observed for OC use before age 25 or before first full-term pregnancy, or in relation to duration of use, recency of use, or time since first use. Analysis of the subgroup of women less than 45 years of age also showed no relationship between OC use and breast cancer risk. However, an elevated risk of breast cancer was observed among nulliparous women with 5 or more years of OC use in comparisons with hospital controls (odds ratio 7.8) and community controls (odds ratio 2.3). This analysis was based on small numbers of subjects and the 95% confidence intervals touched or overlapped with 1. An unexpected association between duration of OC use and breast cancer risk was found among older premenopausal women in comparisons of cases with both control groups. For these women, a trend was evident in the odds ratio by duration of OC use, and the comparison between cases and community controls was statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Follicle-stimulating hormone concentrations in relation to active and passive smoking.

OBJECTIVE: To determine the association between various forms of tobacco exposure and ovarian status, as measured by FSH concentrations, in women 38-49 years old. METHODS: Two hundred ninety women between 38-49 years old, who had not had hysterectomy or oophorectomy, completed a self-administered questionnaire that included information on tobacco exposure and had serum FSH levels measured on days 2-4 of the menstrual cycle. Linear regression was used to assess the relation between FSH and tobacco exposure. RESULTS: Controlling for age and other factors, FSH concentrations were 66% higher among current smokers (geometric mean FSH 14.0 mIU/mL) and 39% higher among nonsmokers with passive smoke exposure (11.7 mIU/mL), compared to nonsmoking women without passive smoke exposure (8.4 mIU/mL). The estimated increase in FSH for each year of age was greater for current smokers than for nonsmokers (16 versus 6%, respectively). Ex-smokers did not have higher FSH concentrations, and there was no association between prenatal exposure to tobacco smoke and FSH. CONCLUSION: Both active and passive smoking are associated with elevated FSH concentrations in women 38-49 years old. The effect, limited to women with current exposure, is consistent with a shorter duration of the menopausal transition period.

Does workplace health promotion decrease medical claims?

We examined the relationship between workplace health promotion and medical claims in 38 textile plants, considering also the effects of demographic and contextual variables (i.e., average worker age, sex ratio, racial composition, plant product, and access to medical services). Number of claims per worker varied threefold among plants but was independent of plant workforce's sex ratio, racial composition, and access to medical services. Worker age predicted claims; in a linear regression model, age, sex, race, plant product, and access explained 23% of variance in claims. Health promotion was also related to claims, and its inclusion in the model (with interaction terms involving plant product) explained 54% of variance in claims, with the deletion of race, sex, and access from the reduced model. We concluded that effective health promotion must address the contexts of different types of plant product.

Links between hormone replacement therapy and neoplasia.

OBJECTIVE: To evaluate the literature on exogenous estrogens and progestins on risk of breast and endometrial cancers. DESIGN: Review of epidemiologic literature. SETTING: Population- and hospital-based studies. SUBJECTS: Postmenopausal women. INTERVENTIONS: Sex steroid hormone in hormone replacement regimens. MAIN OUTCOME MEASURES: Breast carcinoma and endometrial carcinoma. RESULTS: Estrogens cause cell proliferation in in vitro systems and enhance tumor formation in carcinogen-exposed animal models. Estrogen effects in humans vary by tissue type, exposure patterns, and subject groups. Doses commonly used for estrogen replacement therapy (ERT) are sufficient to cause proliferation, hyperplasia, and carcinoma of the endometrium. After 10 to 15 years of estrogen use, endometrial cancer risk increases nearly 10-fold, but the cancers produced are generally of low grade and stage with an excellent prognosis. Adding a progestin for > or = 10 d/mo reduces or eliminates the estrogen-induced risk. Breast tissue responds differently to sex steroid hormones. Long-term estrogen use increases breast cancer risk modestly (relative risk approximately 1.3 to 1.5). Particular subgroups, such as those with family history, benign proliferative disease, or late natural menopause, may experience greater risk. None of these characteristics are sufficiently well defined to be clear-cut contraindications to ERT. Adding a progestin does not improve the situation; relative risks may be higher for estrogen plus progestin than for estrogen alone. The effect of low dose progestin, e.g., 2.5 mg Provera, administered continuously with the estrogen, is not known. A small increase in relative risk has a large impact on number of women developing breast cancer because of the high baseline rates. For U.S. women age 65, the baseline rate is 210 new cases per 100,000 women per year. A relative risk as small as 1.2 increases a women's chances of developing breast cancer each year from 1 in 250 to 1 in 200.

Cigarette smoking and sperm density: a meta-analysis.

OBJECTIVE: To quantify, through meta-analysis techniques, the association between cigarette smoking and sperm density. METHODS: The logarithm of the ratio of mean sperm density for smokers to that for nonsmokers for the studies included in this meta-analysis was regressed against a constant, an indicator of study population source (infertility clinic patients or normal men), minimum number of cigarettes smoked per day among smokers (< 10, > or = 10), exclusion of azoospermic men (yes/no), number of semen specimens analyzed (one versus two), and blinding of laboratory personnel to the smoking status of the study participants (yes/no). Regression analyses were performed both unweighted and weighted inversely by study size. A qualitative and quantitative assessment of the relationship between the numbers of cigarettes smoked per day and sperm density was performed. RESULTS: Results of the meta-analysis indicate that smokers' sperm density is on average 13% to 17% (95% confidence interval = 8.0, 21.5) lower than that of nonsmokers. No other factors besides cigarette smoking were found to be independent predictors of sperm density. No clear dose-response relationships between the numbers of cigarettes smoked per day and sperm density emerged. Research conducted by the authors supports the findings of the meta-analysis. CONCLUSION: Cigarette smoking is associated with lowered sperm density. The inconsistency in the literature with regard to this conclusion appears to be the result of small sample sizes in most studies.