Behavior, synaptic mitochondria, and microglia are differentially impacted by chronic adolescent stress and repeated endotoxin exposure in male and female rats.

Early life adversity and chronic inflammation have both been associated with cognitive impairment and neural compromise. In this study, we investigated the interactions between a history of chronic adolescent stress (CAS) and repeated endotoxin exposure on behavior, synaptic mitochondria, and microglia in adult male and female Wistar rats. Adult rats from chronic stress and control conditions were exposed to either repeated endotoxin (lipopolysaccharide; LPS) or saline injections every 3 days for 9 weeks. In both sexes, repeated LPS, regardless of stress history, impaired working memory in the Y maze. Regarding spatial memory, LPS impaired function for females; whereas, CAS altered function in males. Although males had an increase in anxiety-like behavior shortly after CAS, there were no long-term effects on anxiety-like behavior or social interaction observed in males or females. Stress did not alter synaptic mitochondrial function in either sex. Repeated LPS altered synaptic mitochondrial function such that ATP production was increased in females only. There were no observed increases in IBA-1 positive cells within the hippocampus for either sex. However, LPS and CAS altered microglia morphology in females. Impact of repeated LPS was evident at the terminal endpoint with increased spleen weight in both sexes and decreased adrenal weight in males only. Circulating cytokines were not impacted by repeated LPS at the terminal endpoint, but evidence of CAS effects on cytokines in females were evident. These data suggest a long-term impact of chronic stress and an impact of repeated endotoxin challenge in adulthood; however, not all physiological and behavioral metrics examined were impacted by the paradigm employed in this study and the two environmental challenges rarely interacted.

Chronic stress beginning in adolescence decreases spatial memory following an acute inflammatory challenge in adulthood.

Prolonged stress beginning in adolescence can contribute to the dysregulation of the neuroendocrine system in adulthood. As the neuroendocrine and neuroimmune systems participate in bi-directional regulatory control, adolescent stress can prime the neuroimmune system to future inflammatory insults. Previous work from our group demonstrates that stress exaggerates the hippocampal response to inflammation, which can lead to deficits in learning and memory. In the current study, we sought to interrogate the interaction between an acute peripheral challenge of lipopolysaccharide (LPS) in male and female Wistar rats with a history of stress beginning in adolescence (CAS). Males from the CAS group were more vulnerable to the peripheral effects of LPS compared to non-stressed males including porphyrin staining and ruffled fur. In contrast, LPS generated similar peripheral effects in females regardless of adolescent stress history. Learning and memory were differentially impacted by LPS as a function of stress history and effects manifested differently when stratified by sex. Males with a history of adolescent stress exhibited deficits in initial learning. Females from the CAS group performed similar to controls during acquisition but exhibited a slight impairment during reversal learning. Males and females with a history of stress displayed memory impairment during the probe assessments as compared to their same-sex control group. We conclude that while stress beginning in adolescence enhanced the vulnerability of learning and memory to an inflammatory challenge, the phenotype of this effect manifested differently in males and females. These data demonstrate a sustained impact of adolescent stress on the neuroimmune system which is sufficient to influence cognitive performance in both sexes.

Chronic adolescent stress causes sustained impairment of cognitive flexibility and hippocampal synaptic strength in female rats.

Females that experience chronic stress during development, particularly adolescence, are the most vulnerable group to stress-induced disease. While considerable attention has been devoted to stress-induced manifestation of anxiety, depression, and PTSD, evidence indicates that a history of chronic stress is also a risk factor for cognitive decline and dementia - with females again in a higher risk group. This interplay between sex and stress history indicates specific mechanisms drive neural dysfunction across the lifespan. The presence of sex and stress steroid receptors in the hippocampus provides a point of influence for these variables to drive changes in cognitive function. Here, we used a rodent model of chronic adolescent stress (CAS) to determine the extent to which CAS modifies glutamatergic signaling resulting in cognitive dysfunction. Male and female Wistar rats born in-house remained non-stressed (NS), unmanipulated aside from standard cage cleaning, or were exposed to either physical restraint (60 min) or social defeat (CAS) each day (6 trials each), along with social isolation, throughout the adolescent period (PND 35-47). Cognition was assessed in adult (PND 80-130) male and female rats (n = 10-12) using the Barnes Maze task and the Attention Set-Shift task. Whole hippocampi were extracted from a second cohort of male and female rats (NS and CAS; n = 9-10) and processed for RNA sequencing. Brain tissue from the first cohort (n = 6) was processed for density of glutamatergic synaptic markers (GluA1, NMDA1a, and synaptophysin) or whole-cell patch clamping (n = 4) to determine glutamatergic activity in the hippocampus. Females with a history of chronic stress had shorter latencies to locate the goal box than NS controls during acquisition learning but showed an increased latency to locate the new goal box during reversal learning. This reversal deficit persisted across domains as females with a history of stress required more trials to reach criterion during the reversal phases of the Attention Set-Shift task compared to controls. Ovariectomy resulted in greater performance variability overall during reversal learning with CAS females showing worse performance. Males showed no effects of CAS history on learning or memory performance. Bioinformatic prediction using gene ontology categorization indicated that in females, postsynaptic membrane gene clusters, specifically genes related to glutamatergic synapse remodeling, were enriched with a history of stress. Structural analysis indicated that CAS did not alter glutamate receptor density in females. However, functionally, CAS females had a decreased AMPA/NMDA-dependent current ratio compared to controls indicating a weakening in synaptic strength in the hippocampus. Males showed only a slight change in density of NMDA1a labeling in the CA3 region with a history of stress. The data observed here suggest that females are at risk for impaired cognitive flexibility following a history of adolescent stress, possibly driven by changes in glutamatergic signaling.

High-fructose diet during adolescent development increases neuroinflammation and depressive-like behavior without exacerbating outcomes after stroke.

Diseases, disorders, and insults of aging are frequently studied in otherwise healthy animal models despite rampant co-morbidities and exposures among the human population. Stressor exposures can increase neuroinflammation and augment the inflammatory response following a challenge. The impact of dietary exposure on baseline neural function and behavior has gained attention; in particular, a diet high in fructose can increase activation of the hypothalamic-pituitary-adrenal axis and alter behavior. The current study considers the implications of a diet high in fructose for neuroinflammation and outcomes following the cerebrovascular challenge of stroke. Ischemic injury may come as a "second hit" to pre-existing metabolic pathology, exacerbating inflammatory and behavioral sequelae. This study assesses the neuroinflammatory consequences of a peri-adolescent high-fructose diet model and assesses the impact of diet-induced metabolic dysfunction on behavioral and neuropathological outcomes after middle cerebral artery occlusion. We demonstrate that consumption of a high-fructose diet initiated during adolescent development increases brain complement expression, elevates plasma TNFα and serum corticosterone, and promotes depressive-like behavior. Despite these adverse effects of diet exposure, peri-adolescent fructose consumption did not exacerbate neurological behaviors or lesion volume after middle cerebral artery occlusion.

Paper or Plastic? Exploring the Effects of Natural Enrichment on Behavioural and Neuroendocrine Responses in Long-Evans Rats.

Enriched environments are beneficial to neurobiological development; specifically, rodents exposed to complex, rather than standard laboratory, environments exhibit evidence of neuroplasticity and enhanced cognitive performance. In the present study, the nature of elements placed in the complex environment was investigated. Accordingly, rats (n = 8 per group) were housed either in a natural environment characterised by stimuli such as dirt and rocks, an artificial environment characterised by plastic toys and synthetic nesting materials, a natural/artificial environment characterised by a combination of artificial and natural stimuli or a laboratory standard environment characterised by no enrichment stimuli. Following exposure to emotional and cognitive behavioural tasks, including a cricket hunting task, a novel object preference task and a forced swim task, brains were processed for glial fibrillary acidic protein (GFAP)-, neuronal nuclei (NeuN)- and brain-derived neurotrophic factor (BDNF) immunoreactivity. Baseline and stress foecal samples were collected to assess corticosterone (CORT) and dehydroepiandrosterone (DHEA). Natural environment animals exhibited shorter diving latencies and increased diving frequencies in the second forced swimming task, along with higher DHEA/CORT ratios, and higher GFAP immunoreactivity in the hippocampus. The type of environmental enrichment did not influence levels of BDNF immunoreactivity in the CA1, CA3 and dentate gyrus of the hippocampus; however, natural environment animals exhibited higher levels of NeuN immunoreactivity in the retrosplenial cortex, an area involved in spatial memory and other cognitive functions. These results suggest that, in addition to enhancing behavioural and endocrinological variables associated with resilience, exposure to natural stimuli might alter plasticity in brain areas associated with cortical processing and learning.

Neurogenesis and anxiety-like behavior in male California mice during the mate's postpartum period.

Our understanding of postpartum anxiety (PPA) in fathers is limited, despite the negative consequences of anxiety on the father and child. Offspring contact reduces PPA in mothers; however, parallel investigations in fathers has gone unaddressed. Adult neurogenesis in the dentate gyrus (DG) contributes to anxiety regulation and is altered during the postpartum period, yet the effects of fatherhood on the production, or survival, of newborn cells in the DG, and the role of adult neurogenesis in PPA regulation, have not been examined. Using the biparental California mouse (Peromyscus californicus), we examined the relationships among postnatal day, anxiety-like behavior and adult neurogenesis in fathers. We hypothesized that attenuated anxiety-like behavior and enhanced adult neurogenesis would be observed when father-offspring contact was increased. We observed a reduction in anxiety-like behavior on the elevated plus-maze, but only at PND 16, a time of peak pup retrieval. Fatherhood reduced 1-week survival of newborn cells; however, surviving cells were maintained until 2 weeks postpartum. In contrast, non-fathers experienced a significant reduction in the survival of newborn cells between 1 and 2 weeks postpartum. Fatherhood also increased the numbers of newborn cells that expressed a neuronal phenotype. Collectively, these findings suggest that offspring interaction contributes to reductions in anxiety-like behavior and the maintenance of newborn neurons in the DG of fathers. These data contribute to our knowledge of the postpartum affective state in fathers, findings that may contribute to improved health of both the father and offspring.

Prenatal diethylstilbestrol exposure and risk of obesity in adult women.

Diethylstilbestrol (DES) is a non-steroidal estrogen that was commonly prescribed during pregnancy from the late 1940s to 1971. A potent endocrine disruptor, prenatal DES exposure has been linked with reproductive tract malformations, adverse pregnancy outcomes, cancer, infertility and earlier menopause. DES was used for years as a growth promoter in animal production. Some animal studies suggest that prenatal DES exposure is associated with obesity and metabolic disturbances. Using data from the National Cancer Institute DES Follow-Up Study, we evaluated the association between DES and adult obesity, weight gain from age 20 to mid-life, central adiposity and height among 2871 prenatally exposed and 1352 unexposed women between 23 and 52 years of age (median 41.5) at baseline in 1994. DES exposure status was confirmed by prenatal medical record review. We used multivariable log-binomial models to calculate risk ratios (RRs) for obesity in 2006, and linear regression to calculate mean differences in body mass index, weight gain, waist circumference and height. The adjusted RR for DES and obesity was 1.09 [95% confidence interval (CI): 0.97, 1.22], and RRs were 1.23 (CI: 1.07, 1.42) and 1.05 (CI: 0.91, 1.20) for low and high estimated total DES dose, respectively, compared with no exposure. DES-exposed women gained slightly more weight than unexposed women [mean difference, 0.70 kg (CI: -0.27, 1.66)]. This study suggests that prenatal DES exposure may be associated with a small increase in adult obesity.

Modeling paternal attentiveness: distressed pups evoke differential neurobiological and behavioral responses in paternal and nonpaternal mice.

With the exception of parturition and lactation, male California deer mice (Peromyscus californicus) exhibit the same parental responses toward offspring as conspecific females. A closely related species, Peromyscus maniculatus, however, rarely exhibits paternal responses. In the current study, a comparative species approach was used to assess paternal responses in both Peromyscus species with varying levels of paternal experience (biological fathers, pup-exposed virgins, and pup-naïve virgins). Of special interest was the persistence of the males to direct their attention toward a distressed pup housed in a small enclosure (i.e., a barrier existed between males and pups). In addition to pup-directed responses, non-pup-directed responses such as grooming, resting and jumping were recorded. Subsequently, all animals' brains were assessed for fos-immunoreactivity (ir) in several areas previously associated with the paternal brain circuit. Overall, P. californicus exhibited more pup-directed responses as well as less fos-ir in brain areas involved in emotional integration and processing such as the insula and anterior cingulate. In addition to increased activation of emotional regulatory areas, P. maniculatus males, observed to direct their behavior away from the pup, exhibited higher fos-ir in the nucleus accumbens (involved in goal acquisition), perhaps due to a heightened motivation to avoid the pups. Interestingly, experience with pups altered the lateral septum and amygdala activation of P. maniculatus to levels similar to P. californicus biological fathers. Finally, fos-ir was increased in the medial preoptic area, involved in the maintenance of maternal behavior, in the biological fathers of both species. Thus, although biological predispositions toward pup-directed behaviors were observed in P. californicus males, evidence of a few shifts toward the paternal neural activation profile was apparent in P. maniculatus males. Specifically, modifications in fear responses and social processing may represent the cornerstones of the gradual shift from social tentativeness to social attentiveness in the presence of pups.

Birth defects in the sons and daughters of women who were exposed in utero to diethylstilbestrol (DES).

Prenatal exposure to diethylstilbestrol (DES) is associated with adverse health outcomes, including anatomic anomalies of the reproductive tract in women and of the genitourinary tract in men. The mouse model, which replicates many DES-related effects seen in humans, suggests that prenatal DES exposure causes alterations that may affect the next generation of offspring. We asked women participating in a large, multi-centre study of prenatal DES exposure to report birth defects occurring among 4029 sons and 3808 daughters (i.e., the third generation). A subcohort of 793 third generation daughters was also queried for birth defects. We used logistic regression models to generate odds ratio and 95% confidence intervals for the association between prenatal DES exposure in the mother and birth defects in the offspring. Based on the mothers' reports, overall birth defects were elevated in the sons (OR = 1.53; 95% CI = 1.04, 2.23) and in the daughters (OR = 2.35; 95% CI = 1.44, 3.82). Most estimates of association were imprecise, but daughters appeared to have an excess of heart conditions (OR = 4.56; 95% CI = 1.27, 16.34). Our data suggest a possible association between the mother's prenatal DES exposure and birth defects in their offspring, particularly in daughters. We cannot, however, rule-out the possible influence of reporting bias. In particular, the exposed daughters' elevated risk of cardiac defects may be as a result of the underreporting of these conditions by unexposed mothers.

Combined therapeutic use of AdGFPFasL and small molecule inhibitors of ceramide metabolism in prostate and head and neck cancers: a status report.

As of January 2005, there were 1020 gene therapy clinical trials ongoing worldwide with 675 or 66.2% devoted to cancer gene therapy. The majority are occurring in the US and Europe (http://www.wiley.co.uk/genetherapy/clinical/). At the present time, to our knowledge there are no trials that employ gene delivery of Fas Ligand (FasL). As an important note, and in contrast to somatic cell therapy trials, there are no reported deaths due to therapeutic vector administration in any cancer gene therapy trial. That said, from our studies and from the published literature, the issue of gene delivery remains the major obstacle to successfully employing gene therapy for cancer treatment. Numerous laboratories are studying this with many different approaches. My co-workers and I have focused on the delivery issue by using various approaches that address tumor targeting and transgene expression. In addition, we are focusing on enhancing tumor cell killing via the bystander effect and through use of small molecules to enhance bystander activity.

Mortality in women given diethylstilbestrol during pregnancy.

We used Cox regression analyses to assess mortality outcomes in a combined cohort of 7675 women who received diethylstilbestrol (DES) through clinical trial participation or prenatal care. In the combined cohort, the RR for DES in relation to all-cause mortality was 1.06 (95% CI = 0.98-1.16), and 1.11 (95% CI = 1.02-1.21) after adjusting for covariates and omitting breast cancer deaths. The RR was 1.07 (95% CI = 0.94-1.23) for overall cancer mortality, and remained similar after adjusting for covariates and omitting breast cancer deaths. The RR was 1.27 (95% CI = 0.96-1.69) for DES and breast cancer, and 1.38 (95% CI=1.03-1.85) after covariate adjustment. The RR was 1.82 in trial participants and 1.12 in the prenatal care cohort, but the DES-cohort interaction was not significant (P = 0.15). Diethylstilbestrol did not increase mortality from gynaecologic cancers. In summary, diethylstilbestrol was associated with a slight but significant increase in all-cause mortality, but was not significantly associated with overall cancer or gynaecological cancer mortality. The association with breast cancer mortality was more evident in trial participants, who received high DES doses.

Birth weight and breast cancer risk.

Exploring whether the positive association between birth weight and breast cancer risk differs by other breast cancer risk factors may help inform speculation about biological mechanism. In these data, high birth weight was associated with breast cancer risk in younger and in more educated women, but was not associated overall.

Incidence of squamous neoplasia of the cervix and vagina in women exposed prenatally to diethylstilbestrol (United States).

OBJECTIVES: Women exposed prenatally to diethylstibestrol (DES) have an excess risk of clear-cell adenocarcinoma of the vagina and cervix, but the effect on the incidence of squamous neoplasia is uncertain. The purpose of the current study was to evaluate the long-term risk of developing high-grade squamous neoplasia of the genital tract among women exposed prenatally to DES. METHODS: A cohort comprising 3,899 DES-exposed and 1,374 unexposed daughters was followed for 13 years (1982 1995) for pathology-confirmed diagnoses of high-grade squamous intraepithelial neoplasia (HSIL) of the genital tract. Poisson regression analysis was used to compute relative risks (RR) and 95% confidence intervals (95% CI), adjusting for age, calendar year, and other covariates. RESULTS: The RR (95% CI) among DES-exposed versus unexposed, based on 111 cases of high-grade disease, was 2.1 (1.2-3.8). Adjustment for screening history estimated by the number of years since the last Pap smear had little effect. Risk estimates were higher with earlier intrauterine exposure; the RR (95% CI) for exposure within 7 weeks of the last menstrual period was 2.8 (1.4-5.5). Only two cases of invasive squamous cervical cancer occurred in total, precluding separate analysis. CONCLUSIONS: The findings support an association between in-utero DES exposure and high-grade squamous neoplasia, although a role for more intensive screening among DES-exposed women in the production of this excess could not be completely ruled out.

The use of Fas Ligand, TRAIL and Bax in gene therapy of prostate cancer.

Prostate cancer is the second leading cause of cancer death in the United States. Treatment options for confined disease are generally successful in prolonging life but long-term cures (10-15 years) are elusive for the majority of patients. The prognosis for advanced extra-capsular prostate cancer is grim. However, we are now entering the era of gene therapy options for treatment of prostate cancer. The human genome project coupled with genomics and protemics are providing information that will lead to selection of genes for treatment of prostate cancer. The problem is the science of delivery lags behind knowledge of gene function. Thus, it is important to develop therapies that do not require delivery to 100% of tumor cells but which nevertheless kills the entire cancer by virtue of the bystander effect or other means. This review covers the use, in gene therapy, of apoptotic inducing molecules such as Fas Ligand, and TRAIL which are believed to induce bystander killing activity and Bax which also may function in a similar way.

Intracellular Fas ligand expression causes Fas-mediated apoptosis in human prostate cancer cells resistant to monoclonal antibody-induced apoptosis.

Several laboratories have attempted with little success to induce Fas-mediated apoptosis in prostate cancer (PCa) cells, using different external Fas agonists, i.e., anti-Fas antibodies and membrane-bound FasL. The present study confirms these earlier results using the anti-Fas antibody CH-11 in five human PCa cell lines (PPC-1, LNCaP, PC-3, TSU-Pr1, and DU145). However, intracellular murine FasL expression induced Fas-mediated apoptosis in all CH-11-resistant cell lines. Adenovirus (AdGFPFasL(TET)) was used to deliver a Murine FasL-GFP fusion gene into human PCa cells resulting in 70-98% apoptosis at 48 h as determined by the MTS assay. DU145 and PPC-1 cells treated with AdGFPFasL(TET) stained positive for the TUNEL assay, indicating that cell death was via apoptosis. Using immunofluorescent microscopy, Fas and GFPFasL colocalized to the same intracellular compartment. The anti-Fas neutralizing antibody ZB-4 was unable to block AdGFPFasL(TET)-mediated cell death, suggesting that intracellular FasL may ligate Fas within the Golgi and/or endoplasmic reticulum. This is the first evidence suggesting that these two molecules interact prior to cell surface presentation. Collectively, these findings indicate that intracellular GFPFasL expression is superior to CH-11 at inducing Fas-mediated apoptosis in human PCa cells and may allow use of AdGFPFasL(TET) for PCa gene therapy.

Incidence of squamous neoplasia of the cervix and vagina in des-exposed daughters.

PURPOSE: Women exposed to diethylstibestrol (DES) in utero are known to have an excess risk of clear cell adenocarcinoma of the vagina and cervix, in addition to vaginal epithelial changes, but the effect on the incidence of squamous neoplasia is uncertain. This study evaluated the long-term risk of developing high-grade squamous neoplasia of the genital tract among women exposed prenatally to diethylstilbestrol.METHODS: A cohort comprising 3899 DES-exposed and 1374 unexposed daughters was followed for thirteen years (1982-1995) for pathology-confirmed diagnoses of high-grade squamous neoplasia. A pathologist blinded to exposure status reviewed seventy-seven percent of cases. Poisson regression analysis was used to compute relative risks (RR) and 95% confidence intervals (CI) controlling for age, calendar year, screening history and other covariates.RESULTS: The RR (95% CI) among DES-exposed versus unexposed, based on 111 cases of high-grade disease, was 2.12 (1.19-3.77). Adjustment for screening history had little effect, but when the analysis was restricted to a group highly screened before 1982, the risk was reduced. Risk estimates were higher among women exposed earlier in gestation; the RR (95% CI) for exposure within 7 weeks of the last menstrual period was 2.82 (1.43-5.53).CONCLUSIONS: The findings support an association between in utero DES exposure and high-grade squamous neoplasia, although a role for more intensive screening among DES-exposed women in the production of this excess could not be completely ruled out.

Cancer risk in women exposed to diethylstilbestrol in utero.

CONTEXT: The association between in utero exposure to diethylstilbestrol (DES) and clear cell adenocarcinoma (CCA) of the vagina and cervix is well known, yet there has been no systematic study of DES-exposed daughters to determine whether they have an increased risk of other cancers. As many as 3 million women in the United States may have been exposed to DES in utero. OBJECTIVE: To determine whether women exposed to DES in utero have a higher risk of cancer after an average of 16 years of follow-up. DESIGN: A cohort study with mailed questionnaires and medical record review of reported cancer outcomes. PARTICIPANTS: A cohort of 4536 DES-exposed daughters (of whom 81% responded) and 1544 unexposed daughters (of whom 79% responded) who were first identified in the mid-1970s. MAIN OUTCOME MEASURES: Cancer incidence in DES-exposed daughters compared with population-based rates and compared with cancer incidence in unexposed daughters. RESULTS: To date, DES-exposed daughters have not experienced an increased risk for all cancers (rate ratio, 0.96; 95% confidence interval [CI], 0.58-1.56) or for individual cancer sites, except for CCA. Three cases of vaginal CCA occurred among the exposed daughters, resulting in a standardized incidence ratio of 40.7 (95% CI, 13.1-126.2) in comparison with population-based incidence rates. The rate ratio for breast cancer was 1.18 (95% CI, 0.56-2.49); adjustment for known risk factors did not alter this result. CONCLUSIONS: Thus far, DES-exposed daughters show no increased cancer risk, except for CCA. Nevertheless, because exposed daughters included in our study were, on average, only 38 years old at last follow-up, continued surveillance is warranted to determine whether any increases in cancer risk occur during the menopausal years.

Reproducibility studies and interlaboratory concordance for assays of serum hormone levels: estrone, estradiol, estrone sulfate, and progesterone.

We conducted studies to measure sources of assay variability for estrone, estradiol, estrone sulfate, and progesterone for postmenopausal women (n = 5) and for women in the mid-follicular (n = 5) and mid-luteal (n = 5) phases of the menstrual cycle. A single blood sample from each woman was divided into 2.5-ml aliquots and stored at -70 degrees C, and sets of two aliquots were sent at monthly intervals to each of three laboratories (four for progesterone). Each aliquot was analyzed in duplicate. Thus, within each menstrual category, we were able to estimate the components of variance due to variation among women, variation among aliquots, variation among duplicate measurements, and variation among the 4 analysis days. Using the logarithm of assay measurements, we estimated the percentage of variance attributable to variation among women in each menstrual category, 100 rho, is the estimated intraclass correlation. For each assay, 100 rho exceeded 90% for mid-follicular and mid-luteal women. For postmenopausal women, values of 100 rho exceed 84% for estrone in two laboratories. Values of 100 rho were lower for progesterone in postmenopausal women, although a value of 84% was estimated from one laboratory. These studies indicate that estrogen assays over a period of 3 months permit reliable comparisons among women in a given menstrual category. Progesterone measurements are likewise reliable for women in the mid-follicular and mid-luteal phases but somewhat less satisfactory for postmenopausal women. These assessments of variability pertain only to laboratory techniques and do not allow for secular variation in intra-woman hormone levels. Moreover, although these measurements tend to be reliable enough for making comparisons among women, estimates of coefficients of variation for estrogens are about 10% for mid-follicular and mid-luteal phase women and about 11-20% for postmenopausal women. Coefficients of variation for progesterone are about 10% for mid-luteal, 20% for mid-follicular, and 30% for postmenopausal women.

Migration patterns and breast cancer risk in Asian-American women.

BACKGROUND: Breast cancer incidence rates have historically been 4-7 times higher in the United States than in China or Japan, although the reasons remain elusive. When Chinese, Japanese, or Filipino women migrate to the United States, breast cancer risk rises over several generations and approaches that among U.S. Whites. PURPOSE: Our objective was to quantify breast cancer risks associated with the various migration patterns of Asian-American women. METHODS: A population-based, case-control study of breast cancer among women of Chinese, Japanese, and Filipino ethnicities, aged 20-55 years, was conducted during 1983-1987 in San Francisco-Oakland, California, Los Angeles, California, and Oahu, Hawaii. We successfully interviewed 597 case subjects (70% of those eligible) and 966 control subjects (75%). RESULTS: A sixfold gradient in breast cancer risk by migration patterns was observed. Asian-American women born in the West had a breast cancer risk 60% higher than Asian-American women born in the East. Among those born in the West, risk was determined by whether their grandparents, especially grandmothers, were born in the East or the West. Asian-American women with three or four grandparents born in the West had a risk 50% higher than those with all grandparents born in the East. Among the Asian-American women born in the East, breast cancer risk was determined by whether their communities prior to migration were rural or urban and by the number of years subsequently lived in the West. Migrants from urban areas had a risk 30% higher than migrants from rural areas. Migrants who had lived in the West for a decade or longer had a risk 80% higher than more recent migrants. Risk was unrelated to age at migration for women migrating at ages less than 36 years. Ethnic-specific incidence rates of breast cancer in the migrating generation were clearly elevated above those in the countries of origin, while rates in Asian-Americans born in the West approximated the U.S. White rate. CONCLUSIONS: Exposure to Western lifestyles had a substantial impact on breast cancer risk in Asian migrants to the United States during their lifetime. There was no direct evidence of an especially susceptible period, during either menarche or early reproductive life. IMPLICATIONS: Because heterogeneity in breast cancer risk in these ethnic populations is similar to that in international comparisons and because analytic epidemiologic studies offer the opportunity to disentangle correlated exposures, this study should provide new insights into the etiology of breast cancer.