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1.  Vitamin D Deficiency in Reproductive Age Mongolian Women: A Cross Sectional Study 
Vitamin D production is critical not only for rickets prevention but for its role in several chronic diseases of adulthood. Maternal vitamin D status also has consequences for the developing fetus. This study assessed the prevalence of vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D]<20 ng/ml) and insufficiency [25(OH)D = 20–29 ng/ml] in spring, among reproductive age Mongolian women.
Blood was drawn in March and April, 2009 from 420 Mongolian women, 18–44 years of age. Serum 25(OH)D concentrations were measured, anthropometric measurements were performed and information was collected by interview on lifestyle, dietary and reproductive factors. Logarithm-transformed 25(OH)D levels were compared across risk factor categories by analysis of variance. Linear regression analysis was used to assess the independent associations of factors with vitamin D status. Cutaneous vitamin D3 synthesis was assessed between December and July using a standard 7-dehydrocholesterol ampoule model.
The vast majority of women 415 (98.8%) had serum 25(OH)D <20 ng/ml (50 nmol/l) with an additional 4 women (<1%) in the insufficient range (20–29 ng/ml); only one women (0.2%) had sufficient levels (>30 ng/ml or 75 nmol/l). 25(OH)D concentrations were positively and independently associated with educational status and use of vitamin D supplements, but not with other demographic, lifestyle, reproductive, or anthropometric factors. 25(OH)D levels were not associated with dietary factors in this population, as there is little access to foods containing vitamin D in Mongolia. No production of previtamin D3 was observed until March and was maximally effective in April and was sustained through July.
These data suggest that the prevalence of vitamin D deficiency in spring among reproductive age women in Mongolia is high. Given the lack of naturally vitamin D-rich food in the diet and limited use of vitamin D supplements, food fortification and/or supplementation with vitamin D should be considered among these women.
PMCID: PMC3909713  PMID: 24076033
25-hydroxyvitamin D; vitamin D; vitamin D deficiency; healthy women; reproductive age
2.  The Role of Hormones in the Differences in the Incidence of Breast Cancer between Mongolia and the United Kingdom 
PLoS ONE  2014;9(12):e114455.
There are striking differences in breast cancer incidence between Asian and western women. Rates vary substantially within Asia also, with Mongolia's even lower than China's. These profound differences have been speculated to be due in part to diet, mediated by circulating hormone concentrations.
Sex steroid hormone concentrations were measured in women living in Ulaanbaatar, Mongolia and the United Kingdom (U.K.). Diet was obtained by interview and national survey data. Mean hormone differences were compared by country, and systematic variation by number of days since last menstrual period was modeled and adjusted for age and parity; difference in overall area under the curves was assessed.
The diet in Mongolia was higher in meat and dairy than in the U.K. Mean testosterone concentrations were 18.5% lower (p<0.0001) while estradiol concentrations were 19.1% higher (p = 0.02) in Mongolian than British women, adjusted for age and parity. Progesterone was almost 50% higher in Mongolian women (p = 0.04), particularly during the follicular phase and early luteal surge. Hormone concentrations generally were similar in Mongolian women born in Ulaanbaatar compared with those born in rural areas, although there was a decreasing progesterone trend by degree of westernization (rural Mongolia; urban Mongolia; U.K.). Mean hormone differences were similar when restricted to parous women, and with further adjustment for body mass index, height, and smoking status.
These data augment accumulating evidence that circulating estrogens are unlikely to explain reduced breast cancer rates in Asia compared with the west, and suggest casting a wider net with respect to biomarkers. Lower testosterone and higher progesterone in Mongolian women raise the possibility that these hormones may be important to consider. In addition, the almost exclusive dietary reliance of Mongolians on meat and dairy argues against beneficial effects of a low-fat diet on circulating hormones explaining international breast cancer differences.
PMCID: PMC4275167  PMID: 25536229
3.  A comparison of migrants to, and women born in, urban Mongolia: demographic, reproductive, anthropometric and lifestyle characteristics 
International Health  2013;5(4):244-250.
Mongolia has experienced vast migration from rural to urban areas since the 1950s. We hypothesized that women migrating to Ulaanbaatar, the capital, would differ in factors related to future chronic disease risk compared with women who were born in Ulaanbaatar.
Premenopausal mothers (aged <44 years) of children attending two schools (one in the city centre and one in the outskirts) in Ulaanbaatar were recruited for the study. During April and May 2009, 420 women were interviewed about migration, reproductive history and lifestyle factors and anthropometric measurements were taken.
Women born in (n=178) and outside (n=242) Ulaanbaatar were similar in education and marital status, but the latter appeared to have a more traditional lifestyle including being more likely to have lived as a nomadic herder (22.3% vs 5.6%; p<0.001) and to currently live in a traditional yurt or ger (40.1% vs 29.2%). Ever-use of hormonal contraception was more common in women born outside Ulaanbaatar (52.1% vs 38.2%; p=0.005) and their age at first live birth was older (26.0% vs 20.8% for ≥25 vs <25 years). Although the number of pregnancies was similar, the number of live births was greater for those born outside Ulaanbaatar (p=0.002). Women born in Ulaanbaatar were more likely to have smoked cigarettes (24.7% vs 11.2%; p<0.001). Women born outside Ulaanbaatar were more likely to consume the traditional meat and dairy diet.
Rural migrants to Mongolia's capital have retained a traditional lifestyle in some, but not all, respects. Internal migrant populations may provide the opportunity to assess the effect of changes in isolated risk factors for subsequent chronic disease.
PMCID: PMC3850362  PMID: 24021762
Lifestyle; Reproductive factors; Diet; Non-communicable diseases; Mongolia; Asia
4.  A migrant study of pubertal timing and tempo in British-Bangladeshi girls at varying risk for breast cancer 
Earlier menarche is related to subsequent breast cancer risk, yet international differences in the age and tempo of other pubertal milestones and their relationships with body mass index (BMI) are not firmly established in populations at differing risk for breast cancer. We compared age and tempo of adrenarche, thelarche, pubarche, and menarche in a migrant study of Bangladeshi girls to the United Kingdom (UK) and assessed whether differences by migration were explained by differences in BMI.
Included were groups of Bangladeshi (n =168), British-Bangladeshi (n =174) and white British (n =54) girls, aged 5 to 16 years. Interviewer-administered questionnaires obtained pubertal staging; height and weight were measured. Salivary dehydroepiandrosterone-sulfate concentrations >400 pg/ml defined adrenarche. Median ages of pubertal milestones and hazard ratios (HR) with 95% confidence intervals (CI) were estimated from Weibull survival models.
In all three groups, adrenarche occurred earliest, followed by thelarche, pubarche, and finally menarche. Neither median age at adrenarche (Bangladeshi = 7.2, British-Bangladeshi = 7.4, white British = 7.1; P-trend = 0.70) nor at menarche (Bangladeshi = 12.5, British-Bangladeshi = 12.1, white British = 12.6; P-trend = 0.70) differed across groups. In contrast, median age at thelarche (Bangladeshi = 10.7, British-Bangladeshi = 9.6, white British = 8.7; P-trend <0.01) occurred earlier among girls living in the UK. Compared with Bangladeshi girls, HRs (95% CI) for earlier thelarche were 1.6 (1.1 to 2.4) for British-Bangladeshi girls and 2.6 (1.5 to 4.4) for white British girls (P-trend <0.01), but were attenuated after adjustment for BMI (British-Bangladeshi = 1.1 (0.7 to 1.8), white British = 1.7(1.0 to 3.1); P-trend =0.20).
Thelarche occurred earlier, but puberty progressed slower with increasing exposure to the UK environment; differences were partially explained by greater BMI. The growth environment might account for much of the ethnic differences in pubertal development observed across and within countries.
PMCID: PMC4303203  PMID: 25398700
5.  Fetal Growth and Childhood Cancer: A Population-Based Study 
Pediatrics  2013;132(5):e1265-e1275.
The etiology of childhood cancers is largely unknown. Studies have suggested that birth characteristics may be associated with risk. Our goal was to evaluate the risk of childhood cancers in relation to fetal growth.
We conducted a case-control study nested within Nordic birth registries. The study included cancer cases diagnosed in Denmark, Finland, Norway, and Sweden among children born from 1967 to 2010 and up to 10 matched controls per case, totaling 17 698 cases and 172 422 controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were derived from conditional logistic regression.
Risks of all childhood cancers increased with increasing birth weight (Ptrend ≤ .001). Risks of acute lymphoid leukemia and Wilms tumor were elevated when birth weight was >4000 g and of central nervous system tumors when birth weight was >4500 g. Newborns large for gestational age were at increased risk of Wilms tumor (OR: 2.1 [95% CI: 1.2–3.6]) and connective/soft tissue tumors (OR: 2.1 [95% CI: 1.1–4.4]). In contrast, the risk of acute myeloid leukemia was increased among children born small for gestational age (OR: 1.8 [95% CI: 1.1–3.1]). Children diagnosed with central nervous system tumors at <1 year of age had elevated risk with increasing head circumference (Ptrend < .001). Those with head circumference >39 cm had the highest risk (OR: 4.7 [95% CI: 2.5–8.7]).
In this large, Nordic population-based study, increased risks for several childhood tumors were associated with measures of fetal growth, supporting the hypothesis that tumorigenesis manifesting in childhood is initiated in utero.
PMCID: PMC3813399  PMID: 24167169
birth weight; childhood cancer; fetal growth; nested case-control study; Nordic countries
6.  Childhood Environment Influences Adrenarcheal Timing among First-Generation Bangladeshi Migrant Girls to the UK 
PLoS ONE  2014;9(10):e109200.
Adrenarche is a key early life event that marks middle childhood at approximately 7 years of age. Earlier work with British-Bangladeshi migrant women suggested that environmental conditions experienced before adrenarche influence adult reproductive function. We therefore investigated whether Bangladeshi children who migrate to the United Kingdom (UK) reach adrenarche earlier than non-migrants in Bangladesh or the United Kingdom.
Methods and Findings
Healthy girls, aged 5–16 years, were recruited from schools in Sylhet, Bangladesh and London, England comprising four groups: Sylhetis (n = 165), first-generation migrants to the United Kingdom (n = 42), second-generation girls (n = 162), and British girls of European origin (n = 50). Anthropometric measurements were collected together with questionnaire data for migration and socioeconomic characteristics. Saliva samples were assayed for dehydroepiandrosterone (DHEAS) using enzyme-linked immunosorbent assays. Multiple linear regressions tested for group differences in anthropometric and socioeconomic variables and DHEAS levels. Median ages at adrenarche (DHEAS>400 pg/ml) were estimated using Weibull regression models for parametric survival analysis. Hazard ratios for reaching adrenarche earlier and 95% confidence intervals (CI), both unadjusted and adjusted for anthropometric variables, were estimated from the survival analyses. First-generation migrants had a median age at adrenarche (5.3 years) that was significantly earlier than Sylheti (7.2), second-generation (7.4), and European (7.1) girls. In univariate analyses, first-generation girls reached adrenarche significantly earlier than Sylhetis [HR (CI): 2.8 (1.4–5.5]. In multivariate models, first generation girls still reached adrenarche earlier than Sylhetis after adjusting for height [HR(CI): 1.9 (0.9–4.1)] and weight [HR(CI):1.7 (0.8–3.8)], but these results were attenuated.
We suggest that rapid catch-up growth experienced by first generation girls during early childhood may explain their advanced adrenarche. The environmental conditions leading to an earlier adrenarche, as well as the health implications of this early transition, merit further exploration.
PMCID: PMC4195659  PMID: 25309977
7.  A Linked-Registry Study of Gestational Factors and Subsequent Breast Cancer Risk in the Mother 
Women who were younger at their first live birth have a reduced breast cancer risk. Other pregnancy characteristics, including complications, also may affect risk but because they are rare, require large datasets to study.
The association of pregnancy history and breast cancer risk was assessed in a population-based study including 22,646 cases diagnosed in Washington State 1974–2009, and 224,721 controls, frequency matched on parity, age and calendar year of delivery, and race/ethnicity. Information on prediagnosis pregnancies derived from linked birth certificate and hospital discharge databases. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated.
Multiple gestation pregnancies were associated with decreased breast cancer risk (OR 0.65, 95% CI 0.57–0.74) as was prepregnancy obesity (OR 0.76, 95% CI 0.65–0.90). Infant birth weight was positively associated (6% per 1,000 g, 95% CI 3%–9%). The ORs for first trimester bleeding (OR 3.35, 95% CI 1.48–7.55) and placental abnormality/insufficiency (OR 2.24, 95% CI 1.08–4.67) were increased in women diagnosed at age 50+ years and 15+ years after the index pregnancy. Results were similar in analyses restricted to first pregnancies, those closest to diagnosis, and when excluding in situ disease.
These data suggest that multiple gestation pregnancies are protective, whereas delivering larger infants increases risk for later development of maternal breast cancer. Placental abnormalities that result in bleeding in pregnancy also may reverse the long-term protection in postmenopausal women associated with parity.
Certain pregnancy characteristics appear to be associated with later maternal breast cancer risk.
PMCID: PMC3650095  PMID: 23592822
breast cancer; gestational factors; birth certificate; cancer registry; pregnancy
8.  Genome-wide Association Study Identifies Two Susceptibility Loci for Osteosarcoma 
Nature genetics  2013;45(7):799-803.
Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. In order to better understand the genetic etiology of osteosarcoma, we performed a multi-stage genome-wide association study (GWAS) consisting of 941 cases and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: rs1906953 at 6p21.3, in the glutamate receptor metabotropic 4 [GRM4] gene (P = 8.1 ×10-9), and rs7591996 and rs10208273 in a gene desert on 2p25.2 (P = 1.0 ×10-8 and 2.9 ×10-7). These two susceptibility loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma.
PMCID: PMC3910497  PMID: 23727862
9.  Breast cancer incidence in Mongolia 
Cancer causes & control : CCC  2012;23(7):1047-1053.
Data on international variation in breast cancer incidence may help to identify additional risk factors. Substantially lower breast cancer rates in Asia than in North America and Western Europe are established, but differences within Asia have been largely ignored despite heterogeneity in lifestyles and environments. Mongolia’s breast cancer experience is of interest because of its shared genetics but vastly different diet compared with other parts of Asia.
Age-standardized breast cancer incidence and mortality rates obtained from the International Association of Cancer Registries are presented for several Asian countries. Mongolian incidence rates obtained from its cancer registry describe incidence within the country.
Breast cancer incidence in Mongolia (age standardized 8.0/100,000) is almost a third of rates in China (21.6/100,000), and over five times that of Japan (42.7/100,000) and Russia (43.2/100,000). Rates within Mongolia appear to have increased slightly over the last decade and are higher in urban than rural areas (annual percentage increase of age-standardized rates from 1998 to 2005 was 3.60 and 2.57%, respectively). The increase in breast cancer incidence with age plateaus at menopause, as in other Asian populations.
Mongolia’s low breast cancer incidence is of particular interest because of their unusual diet (primarily red meat and dairy) compared with other Asian countries. More intensive study of potential dietary, reproductive and lifestyle factors in Mongolia with comparison to other Asian populations may provide more clarity in what drives the international breast cancer rate differences.
PMCID: PMC3786577  PMID: 22543542
Mongolia; Breast cancer; Urban-rural; Asia; International
10.  Height at diagnosis and birth-weight as risk factors for osteosarcoma 
Cancer causes & control : CCC  2011;22(6):899-908.
Osteosarcoma typically occurs during puberty. Studies of the association between height and/or birth-weight and osteosarcoma are conflicting. Therefore, we conducted a large pooled analysis of height and birth-weight in osteosarcoma.
Patient data from 7 studies of height, and 3 of birth-weight were obtained, resulting in 1067 cases with height and 434 cases with birth-weight data. We compared cases to the 2000 US National Center for Health Statistics Growth Charts by simulating 1000 age and gender matched controls per case. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between height or birth-weight and risk of osteosarcoma for each study were estimated using logistic regression. All of the case data were combined for an aggregate analysis.
Compared to average birth-weight subjects (2665–4045g), individuals with high birth-weight (≥4046g) had an increased osteosarcoma risk (OR 1.35, 95%CI 1.01–1.79). Taller than average (51st–89th percentile) and very tall individuals (≥90th percentile) had an increased risk of osteosarcoma (OR 1.35, 95%CI 1.18–1.54, and OR 2.60, 95%CI 2.19–3.07, respectively; Ptrend <0.0001).
This is the largest analysis of height at diagnosis and birth-weight in relation to osteosarcoma. It suggests that rapid bone growth during puberty and in utero contributes to OS etiology.
PMCID: PMC3494416  PMID: 21465145
osteosarcoma; height; birth-weight; meta-analysis; epidemiology
11.  Associations of Pregnancy Characteristics with Maternal and Cord Steroid Hormones, Angiogenic Factors, and Insulin-like Growth Factor Axis 
Cancer causes & control : CCC  2011;22(11):1587-1595.
The objective of this study was to comprehensively profile biological factors in pregnancy that have been postulated to be important components of the in utero environment and may also have relevance to later susceptibility to cancer and other chronic diseases.
Steroid sex hormones, IGFs, and angiogenic factors were measured in maternal and cord serum from term, normotensive pregnancies. Spearman correlations and linear regression estimated relationships among the biological factors and clinical characteristics.
The analytes were generally not correlated between maternal and fetal circulations. However, significant correlations were demonstrated among several analytes within maternal or cord samples. A few analytes were associated with clinical characteristics (e.g., maternal IGF-1and IGFBP-3 were inversely correlated with offspring birth weight, while maternal leptin and cord testosterone were positively correlated with this characteristic). Maternal androgens were higher in African-Americans than whites and maternal PlGF and soluble fms-like tyrosine kinase-1 (sFlt-1) were higher in male than female offspring.
There were significant correlations among analytes but the patterns differed depending on whether they were measured in the maternal or fetal circulation. The number and magnitude of correlations among analytes, however, should affect the design and interpretation of future studies.
PMCID: PMC3321929  PMID: 21947778
African-American; angiogenic factors; IGF; leptin; prolactin
12.  Maternal Angiogenic Profile in Pregnancies that Remain Normotensive 
We sought to determine if maternal characteristics are associated with angiogenic profile in the first and second trimester of normotensive pregnancies.
Study Design
Circulating levels of maternal placental like growth factor (PlGF), soluble fms-like tyrosine kinase receptor (sFlt1), and soluble endoglin (sEng) were measured in serum samples collected during the first (median 11.3 weeks) and second trimester (median 17.1 weeks) of 182 normotensive pregnancies. Diastolic blood pressure (DBP), systolic blood pressure (SBP), and mean arterial pressure (MAP) were measured at the same visits when samples were collected to measure angiogenic factors. Linear regression analysis was used to examine associations of the angiogenic measures with maternal characteristics. The association between blood pressure measures and concentrations of angiogenic factors was evaluated using Spearman correlation and linear regression analysis.
In adjusted analyses, nulliparous women had higher sFlt1 concentrations in both first (P=0.06) and second (P=0.001) trimester. Higher BMI was associated with greater sFlt1 concentrations in both the first (P=0.004) and second trimester (P=0.008), but significantly lower sEng concentrations in both trimesters (P=0.002 for first trimester and P=0.0009 for second). Nulliparity and higher BMI also were associated with higher sFlt1/PLGF anti-angiogenic ratios in both first (p=0.05 and p=0.007, respectively) and second trimesters (p=0.003 and p=0.02, respectively). First trimester sFlt1 levels were weakly correlated with first trimester SBP (rs=0.18, p=0.03) and MAP (rs=0.16, p=0.04). Second trimester sEng levels were inversely associated with second trimester MAP (rs= −0.17, p=0.05). Including blood pressure measures in the linear regression models did not change the reported associations of angiogenic factors with maternal characteristics.
These results demonstrate that even early in normotensive pregnancies maternal characteristics are associated with variations in angiogenic profile across this population.
PMCID: PMC3302581  PMID: 21641103
Pregnancy; angiogenic factors; sFlt1; PlGF; soluble endoglin; maternal
13.  Preterm Birth, Fetal Growth, and Age at Menarche among Women Exposed Prenatally to Diethylstilbestrol (DES) 
Diethylstilbestrol (DES), a synthetic estrogen used in pregnancy during the 1950s and 1960s, provides a model for potential health effects of endocrine disrupting compounds in the environment. We evaluated prenatal exposure to DES, based on medical record review, in relation to gestational length, fetal growth, and age at menarche in 4429 exposed and 1427 unexposed daughters. DES exposure was associated with an increase in preterm birth (odds ratio (OR) = 2.97; 95%CI=2.27, 3.87), and a higher risk of small for gestational age (SGA) (OR=1.61; 95% CI=1.31,1.98). The association between DES exposure and early menarche was borderline, with stronger effects when early menarche was defined as <= 10 years (OR = 1.41 95%CI=0.97, 2.03) than defined as <= 11 years (OR=1.16; 95%CI=0.97, 1.39). This study provides evidence that prenatal DES exposure was associated with fetal growth and gestational length, which may mediate associations between DES and health outcomes in later life.
PMCID: PMC3057340  PMID: 21130156
diethylstilbestrol; early life factors; birth weight; small for gestational age; gestational length; menarche; endocrine disruptors
14.  Autoimmune disease incidence among women prenatally exposed to Diethylstilbestrol 
The Journal of rheumatology  2010;37(10):2167-2173.
Animal studies have suggested that prenatal Diethylstilbestrol (DES) exposure may alter immune system development and function including antigen self-recognition. A cohort study was conducted to investigate whether prenatal DES exposure might influence the incidence of at least some specific autoimmune diseases in women.
Women who were and were not prenatally exposed to DES have been followed for more than 25 years for numerous health outcomes including autoimmune disease. To verify diagnoses, medical records or physician abstracts were requested for all women who reported a diagnosis of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), optic neuritis (ON) and idiopathic thrombocytopenic purpura (ITP). Incidence rates of these autoimmune diseases were compared between women who were or were not prenatally DES-exposed.
Overall there was no increase in verified autoimmune disease among DES-exposed women relative to those who were not exposed (Relative Rate (RR) = 1.2; 95% Confidence Interval (CI): 0.7, 2.1). There was, however, a positive association between prenatal DES exposure and RA among women younger than 45 years (RR = 4.9; 95% CI: 1.1, 21.6) and an inverse association among women who were 45 years and older (RR = 0.1; 95% CI 0.01, 0.7).
Overall, these data provide little support for an association between prenatal DES exposure and development of autoimmune disease. The implication that such exposure may be related to RA in an unusual age-related manner is based on small numbers of cases and warrants further study.
PMCID: PMC2988471  PMID: 20634240
Diethylstilbestrol; Prenatal Exposure; Autoimmune Disease; Prospective study
15.  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.
Women participating in a large multi-center study of prenatal DES exposure were asked to report birth defects occurring among 4,029 sons and 3,808 daughters (i.e., the third generation). A subcohort of 793 third generation daughters were also queried for birth defects. We used logistic regression models to generate odds ratios 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 due to the underreporting of these conditions by unexposed mothers.
PMCID: PMC2874639  PMID: 20002218
Diethylstilbestrol; Prenatal exposure; Maternal exposure; Birth defects; Epigenetic alterations
16.  International osteosarcoma incidence patterns in children and adolescents, middle ages, and elderly persons 
Osteosarcoma incidence rates in the United States peak in adolescence and in the elderly. Whereas international patterns of osteosarcoma incidence in children have been described, those for young, middle age, or elderly adults have not. Using the Cancer Incidence in Five Continents, International Agency for Cancer Research (IARC) database we compared incidence rates for children and adolescents (age 0–24), the middle age group (25–59) and elderly (≥60) persons by world regions and individual countries. Overall, worldwide osteosarcoma incidence rates were quite similar in the younger age groups. The greatest variation in incidence rates was observed in the elderly.
PMCID: PMC3048853  PMID: 19330840
osteosarcoma; bone cancer; epidemiology; incidence
17.  Osteosarcoma incidence and survival rates from 1973 to 2004: Data from the Surveillance, Epidemiology, and End Results Program 
Cancer  2009;115(7):1531-1543.
Osteosarcoma, the most common primary bone tumor, occurs most frequently in adolescents, but a second incidence peak among individuals over age 60 exists. Most osteosarcoma epidemiology studies have been embedded in large analyses of all bone tumors, or focused on cases occurring in adolescence. Detailed descriptions of osteosarcoma incidence and survival specifically, with direct comparisons among subjects of all ages and ethnicities, are not available.
Frequency, incidence and survival rates for 3,482 patients with osteosarcoma from the National Cancer Institute’s population-based Surveillance, Epidemiology, and End Results (SEER) program between 1973 and 2004 are presented by age (0–24, 25–59, and 60–85+ years), race, sex, pathology subtype, stage, and anatomic site.
There were large differences in incidence and survival rates by age. Osteosarcoma incidence in the youngest cases was greatest in the Other race designation, while it was greatest in Blacks and Whites in the middle age and elderly patients, respectively. There was a high percentage of osteosarcoma with Paget’s disease and osteosarcoma as a second or greater cancer among the elderly. Tumor site differences among age groups were noted. Survival rates varied by anatomic site and disease stage, and have not significantly improved from 1984 to 2004.
This comprehensive, population-based description of osteosarcoma, identified important differences in incidence, survival, pathologic subtype, and anatomic site among age groups, and quantified the impact of osteosarcoma in Paget’s disease or as a second cancer on incidence and mortality rates. These findings may have implications in understanding osteosarcoma biology and epidemiology.
PMCID: PMC2813207  PMID: 19197972
osteosarcoma; bone cancer; epidemiology; SEER; incidence; survival
18.  Breast Cancer Screening in Women Exposed In Utero to Diethylstilbestrol 
Journal of Women's Health  2009;18(4):547-552.
To determine if women exposed in utero to diethylstilbestrol (DES) are more likely than unexposed women to receive recommended or additional breast cancer screening examinations.
1994 Diethylstilbestrol-Adenosis (DESAD) cohort data are used to assess the degree of recommended compliance of breast cancer screenings found in 3140 DES-exposed and 826 unexposed women. Participants were enrolled at four sites: Houston, Boston, Rochester, and Los Angeles. Logistic regression modeling was used to analyze mailed questionnaire data that included reported frequency over the preceding 5 years (1990–1994) of breast-self examinations (BSEs), clinical breast examinations (CBEs), and mammograms.
DES-exposed women exceeded annual recommendations for CBEs (aOR 2.20, 95% CI, 1.04-4.67) among women without a history of benign breast disease (BBD) compared with unexposed women. There were no other statistically significant differences between exposed and unexposed women who reported performing BSEs, CBEs (<40 years of age), and mammographies, regardless of BBD history.
The majority of DES-exposed women receive breast cancer screenings at least at recommended intervals, but over two thirds do not perform monthly BSEs. Future efforts should be focused on further educating this and other at-risk populations through mailed reminders and during patient consultations on the benefits of screening examinations.
PMCID: PMC2857514  PMID: 19361323
19.  Pregnancy weight gain is not associated with maternal or mixed umbilical cord estrogen and androgen concentrations 
Cancer causes & control : CCC  2008;20(2):263-267.
The association of maternal weight gain with serum hormone concentrations was explored in 75 women who had healthy, singleton pregnancies. Estradiol, estriol, estrone, androstenedione, testosterone, dehydroepiandrosterone (DHEA) and DHEA sulfate concentrations were measured both in maternal and mixed umbilical cord serum to assess hormone levels in both the maternal and fetal circulation at delivery. Our data show no association of maternal or cord steroid hormone concentrations with pregnancy weight gain. Increased exposure to steroid hormones, especially estrogens, during pregnancy has been hypothesized to play a role in subsequent breast cancer risk for both mother and female offspring. Our results are not consistent with an effect of pregnancy weight gain being mediated by this pathway as reflected by hormone concentrations at the end of pregnancy.
PMCID: PMC2631613  PMID: 18830676
Pregnancy; breast cancer; estrogens; androgens
20.  Blood pressure augmentation and maternal circulating concentrations of angiogenic factors at delivery in preeclamptic and uncomplicated pregnancies 
The objective of the study was to determine whether blood pressure increases are associated with maternal angiogenic factors in uncomplicated and preeclamptic pregnancies.
Study Design
Associations of blood pressure increases from mid- to late pregnancy with maternal serum concentrations of soluble fms-like tyrosine kinase receptor (sFlt1), soluble endoglin (sEng), and placental growth factor (PlGF) at delivery were analyzed in 43 uncomplicated and 44 preeclamptic pregnancies.
In uncomplicated pregnancies, increases in diastolic and mean arterial pressure were inversely associated with PlGF at delivery and positively associated with sEng and sFlt1/PlGF ratio. There were no significant associations between blood pressure increases and angiogenic factor concentrations in preeclampsia.
These data suggest that angiogenic factors are involved in blood pressure modulation in normotensive pregnancy and are consistent with the hypothesis that angiogenic balance plays a role in maternal breast cancer risk reduction associated with mid- to late blood pressure increases in uncomplicated pregnancies.
PMCID: PMC2646178  PMID: 18722574
angiogenic factors; blood pressure; breast cancer; preeclampsia; pregnancy
21.  Urogenital abnormalities in men exposed to diethylstilbestrol in utero: a cohort study 
Environmental Health  2009;8:37.
Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women during the 1940s-70s, has been shown to cause reproductive problems in the daughters. Studies of prenatally-exposed males have yielded conflicting results.
In data from a collaborative follow-up of three U.S. cohorts of DES-exposed sons, we examined the relation of prenatal DES exposure to occurrence of male urogenital abnormalities. Exposure status was determined through review of prenatal records. Mailed questionnaires (1994, 1997, 2001) asked about specified abnormalities of the urogenital tract. Risk ratios (RR) were estimated by Cox regression with constant time at risk and control for year of birth.
Prenatal DES exposure was not associated with varicocele, structural abnormalities of the penis, urethral stenosis, benign prostatic hypertrophy, or inflammation/infection of the prostate, urethra, or epididymus. However, RRs were 1.9 (95% confidence interval 1.1-3.4) for cryptorchidism, 2.5 (1.5-4.3) for epididymal cyst, and 2.4 (1.5-4.4) for testicular inflammation/infection. Stronger associations were observed for DES exposure that began before the 11th week of pregnancy: RRs were 2.9 (1.6-5.2) for cryptorchidism, 3.5 (2.0-6.0) for epididymal cyst, and 3.0 (1.7-5.4) for inflammation/infection of testes.
These results indicate that prenatal exposure to DES increases risk of male urogenital abnormalities and that the association is strongest for exposure that occurs early in gestation. The findings support the hypothesis that endocrine disrupting chemicals may be a cause of the increased prevalence of cryptorchidism that has been seen in recent years.
PMCID: PMC2739506  PMID: 19689815
22.  Secondary Sex Ratio among Women Exposed to Diethylstilbestrol in Utero 
Environmental Health Perspectives  2007;115(9):1314-1319.
Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women during the mid-1900s, is a potent endocrine disruptor. Previous studies have suggested an association between endocrine-disrupting compounds and secondary sex ratio.
Data were provided by women participating in the National Cancer Institute (NCI) DES Combined Cohort Study. We used generalized estimating equations to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the relation of in utero DES exposure to sex ratio (proportion of male births). Models were adjusted for maternal age, child’s birth year, parity, and cohort, and accounted for clustering among women with multiple pregnancies.
The OR for having a male birth comparing DES-exposed to unexposed women was 1.05 (95% CI, 0.95–1.17). For exposed women with complete data on cumulative DES dose and timing (33%), those first exposed to DES earlier in gestation and to higher doses had the highest odds of having a male birth. The ORs were 0.91 (95% C, 0.65–1.27) for first exposure at ≥ 13 weeks gestation to < 5 g DES; 0.95 (95% CI, 0.71–1.27) for first exposure at ≥ 13 weeks to ≥ 5 g; 1.16 (95% CI, 0.96–1.41) for first exposure at < 13 weeks to < 5 g; and 1.24 (95% CI, 1.04–1.48) for first exposure at < 13 weeks to ≥ 5 g compared with no exposure. Results did not vary appreciably by maternal age, parity, cohort, or infertility history.
Overall, no association was observed between in utero DES exposure and secondary sex ratio, but a significant increase in the proportion of male births was found among women first exposed to DES earlier in gestation and to a higher cumulative dose.
PMCID: PMC1964903  PMID: 17805421
diethylstilbestrol; estrogens; endocrine-disrupting chemicals; females; sex ratios

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