Lauren C. Houghton

Childhood Environment Influences Adrenarcheal Timing among First-Generation Bangladeshi Migrant Girls to the UK

Background 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. Conclusions 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.

Comparison of clinical, maternal, and self pubertal assessments: Implications for health studies

BACKGROUND: Most epidemiologic studies of puberty have only 1 source of pubertal development information (maternal, self or clinical). Interpretation of results across studies requires data on reliability and validity across sources. METHODS: The LEGACY Girls Study, a 5-site prospective study of girls aged 6 to 13 years (n = 1040) collected information on breast and pubic hair development from mothers (for all daughters) and daughters (if ≥10 years) according to Tanner stage (T1–5) drawings. At 2 LEGACY sites, girls (n = 282) were also examined in the clinic by trained professionals. We assessed agreement (κ) and validity (sensitivity and specificity) with the clinical assessment (gold standard) for both the mothers’ and daughters’ assessment in the subcohort of 282. In the entire cohort, we examined the agreement between mothers and daughters. RESULTS: Compared with clinical assessment, sensitivity of maternal assessment for breast development was 77.2 and specificity was 94.3. In girls aged ≥11 years, self-assessment had higher sensitivity and specificity than maternal report. Specificity for both mothers and self, but not sensitivity, was significantly lower for overweight girls. In the overall cohort, maternal and daughter agreement for breast development and pubic hair development (T2+ vs T1) were similar (0.66, [95% confidence interval 0.58–0.75] and 0.69 [95% confidence interval 0.61–0.77], respectively), but declined with age. Mothers were more likely to report a lower Tanner stage for both breast and pubic hair compared with self-assessments. CONCLUSIONS: These differences in validity should be considered in studies measuring pubertal changes longitudinally when they do not have access to clinical assessments.

Associations of Breast Cancer Risk Factors with Premenopausal Sex Hormones in Women with Very Low Breast Cancer Risk.

Breast cancer incidence rates are low but rising in urban Mongolia. We collected reproductive and lifestyle factor information and measured anthropometrics and serum sex steroid concentrations among 314 premenopausal women living in Ulaanbaatar, Mongolia. Mean differences in hormone concentrations by these factors were calculated using age-adjusted quadratic regression splines. Estrone and estradiol in college-educated women were, respectively, 18.2% (p = 0.03) and 23.6% (p = 0.03) lower than in high-school-educated women. Progesterone concentrations appeared 55.8% lower (p = 0.10) in women residing in modern housing compared with women living in traditional housing (gers), although this finding was not statistically significant. Testosterone concentrations were positively associated with adiposity and central fat distribution; 17.1% difference (p = 0.001) for highest vs. lowest quarter for body mass index and 15.1% difference (p = 0.005) for waist-to-height ratio. Estrogens were higher in the follicular phase of women who breastfed each child for shorter durations. A distinct hormonal profile was associated with an urban lifestyle in premenopausal, Mongol women. In particular, heavier, more-educated women living in urban dwellings had higher testosterone and lower estrogen and progesterone levels. Higher breast cancer incidence in urban compared with rural women suggest that the hormonal profile associated with a more traditional lifestyle may be protective among Mongol women.

The Role of Hormones in the Differences in the Incidence of Breast Cancer between Mongolia and the United Kingdom

Background There are striking differences in breast cancer incidence between Asian and western women. Rates vary substantially within Asia also, with Mongolias even lower than Chinas. These profound differences have been speculated to be due in part to diet, mediated by circulating hormone concentrations. Methods 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. Findings 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. Interpretation 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.

Potential Intervention Targets in Utero and Early Life for Prevention of Hormone Related Cancers

Hormone-related cancers have long been thought to be sensitive to exposures during key periods of sexual development, as shown by the vulnerability to such cancers of women exposed to diethylstilbestrol in utero. In addition to evidence from human studies, animal studies using new techniques, such as gene knockout models, suggest that an increasing number of cancers may be hormonally related, including liver, lung, and bladder cancer. Greater understanding of sexual development has also revealed the “mini-puberty” of early infancy as a key period when some sex hormones reach levels similar to those at puberty. Factors driving sex hormones in utero and early infancy have not been systematically identified as potential targets of intervention for cancer prevention. On the basis of sex hormone pathways, we identify common potentially modifiable drivers of sex hormones, including but not limited to factors such as obesity, alcohol, and possibly nitric oxide. We review the evidence for effects of modifiable drivers of sex hormones during the prenatal period and early infancy, including measured hormones as well as proxies, such as the second-to-fourth digit length ratio. We summarize the gaps in the evidence needed to identify new potential targets of early life intervention for lifelong cancer prevention.

Comparison of methods to assess onset of breast development in the LEGACY Girls Study: methodological considerations for studies of breast cancer

BackgroundYounger age at onset of breast development, which has been declining in recent decades, is associated with increased breast cancer risk independent of age at menarche. Given the need to study the drivers of these trends, it is essential to validate methods to assess breast onset that can be used in large-scale studies when direct clinical assessment of breast onset is not feasible.MethodsBreast development is usually measured by Tanner stages (TSs), assessed either by physical examination or by mother’s report using a picture-based Sexual Maturation Scale (SMS). As an alternative, a mother-reported Pubertal Development Scale (PDS) without pictures has been used in some studies. We compared agreement of SMS and PDS with each other (n = 1022) and the accuracy of PDS with clinical TS as a gold standard for the subset of girls with this measure (n = 282) using the LEGACY cohort. We further compared prediction of breast onset using ROC curves and tested whether adding urinary estrone 1-glucuronide (E1G) improved the AUC.ResultsThe agreement of PDS with SMS was high (kappa = 0.80). The sensitivity of PDS vs clinical TS was 86.6%. The AUCs for PDS alone and SMS alone were 0.88 and 0.79, respectively. Including E1G concentrations improved the AUC for both methods (0.91 and 0.86 for PDS and SMS, respectively).ConclusionsThe PDS without pictures is a highly accurate, sensitive, and specific method for assessing breast onset, especially in settings where clinical TS is not feasible. In addition, it is comparable to SMS methods with pictures and thus easier to implement in large-scale studies, particularly phone-based interviews where pictures may not be available. Urinary E1G can improve accuracy over than PDS or SMS alone.

Similarity of Serum and Plasma Insulin-like Growth Factor Concentrations

Background Insulin-like growth factors (IGFs) are implicated in many normal physiological processes and pathological states, including cancer. For large consortia projects, it may be necessary to make comparisons among studies with different specimens that were not collected specifically to optimize the measurement of IGFs. Objective This study aimed to compare IGFs in matched serum and plasma samples. Methods We measured IGF-I, IGF-II, insulin-like growth factor-binding protein (IGFBP)-3, C-peptide, and leptin in serum and ethylenediaminetetraacetic–containing-plasma samples obtained concurrently from 30 healthy women aged 64–80 years in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial using chemiluminescent or colorimetric enzyme-linked immune assays. Coefficients of variation (CVs) and correlations were determined. Results Intraassay CVs ranged from 0.4% for IGFBP-3 to 10% for IGF-II. Mean concentrations of all analytes were higher in the serum, but the differences in mean concentrations of the analytes between serum and plasma were all <11%. Concordance correlation coefficients of matched serum/plasma specimens were 0.92, 0.91, 0.82, 0.96, and 0.99 for IGF-I, IGFBP-3, IGF-II, C-peptide, and leptin, respectively. Conclusion IGF concentrations measured in serum and plasma are highly correlated but are consistently slightly higher in serum, suggesting that IGF values should be corrected for systematic bias, particularly in consortial efforts when pooling data derived from different specimens.