Early-pregnancy sex steroid and thyroid function hormones, thyroid autoimmunity, and maternal papillary thyroid cancer incidence in the Finnish Maternity Cohort.

Thyroid cancer more commonly affects women than men and is the third most frequently diagnosed cancer among women of reproductive age. We conducted a nested case-control study within the Finnish Maternity Cohort to evaluate pre-diagnostic sex steroid and thyroid function markers in relation to subsequent maternal papillary thyroid cancer. Cases (n = 605) were women ages 18-44 years, who provided an early-pregnancy (<20 weeks gestation) blood sample and were diagnosed with papillary thyroid cancer up to 11 years afterward. Controls (n = 1185) were matched to cases 2:1 by gestational age, mother's age, and date at blood draw. Odds ratios (ORs) for the associations of serum thyroid peroxidase antibodies (TPO-Ab), thyroglobulin antibodies (Tg-Ab), thyroid stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), progesterone, and estradiol with papillary thyroid cancer were estimated using conditional logistic regression. TPO-Ab and Tg-Ab positivity (>95th percentile among controls) were associated with more than 3-fold (OR = 3.32, 95% confidence interval [CI] 2.33-4.72) and 2-fold (OR = 2.03, 95% CI 1.41-2.93) increased odds of papillary thyroid cancer, respectively. These associations were similar by time since blood draw, parity, gestational age, smoking status, and age and stage at diagnosis. In models excluding TPO-Ab or Tg-Ab positivity, TPO-Ab (quartile 4 vs. 1: OR = 1.66, 95% CI 1.17-2.37, p-trend = .002) and Tg-Ab (quartile 4 vs. 1: OR = 1.74, 95% CI 1.22-2.49, p-trend = .01) levels were positively associated with papillary thyroid cancer. No associations were observed for estradiol, progesterone, TSH, fT3, or fT4 overall. Our results suggest that thyroid autoimmunity in early pregnancy may increase the risk of maternal papillary thyroid cancer.

Associations of tubal ligation and hysterectomy with serum androgen and estrogen metabolites among postmenopausal women in the Women's Health Initiative Observational Study.

PURPOSE: Hysterectomy is associated with subsequent changes in circulating hormone levels, but the evidence of an association for tubal ligation is unclear. We evaluated whether circulating concentrations of androgens and estrogens differ by tubal ligation or hysterectomy status in postmenopausal women from the Women's Health Initiative (WHI)-Observational Study (OS). METHODS: Serum androgens and estrogens were measured in 920 postmenopausal women who did not use menopausal hormone therapy at the time of blood draw, of whom 139 self-reported a history of tubal ligation and 102 reported hysterectomy (with intact ovaries). Geometric mean hormone concentrations (GMs) and 95% confidence intervals (CIs) associated with a history of tubal ligation or hysterectomy (ever/never), as well as time since procedures, were estimated using adjusted linear regression with inverse probability of sampling weights to account for selection. RESULTS: Circulating levels of 12 androgen/androgen metabolites and 20 estrogen/estrogen metabolites did not differ by tubal ligation status. Among women reporting prior hysterectomy compared to women without hysterectomy, we observed lower levels of several androgens (e.g., testosterone (nmol/L): GMyes 0.46 [95% CI:0.37-0.57] vs. GMno 0.62 [95% CI:0.53-0.72]) and higher levels of estrogen metabolites, for example, 2-hydroxyestrone-3-methyl ether (GMyes 11.1 [95% CI:8.95-13.9] pmol/L vs. GMno 8.70 [95% CI:7.38-10.3]) and 4-methoxyestrone (GMyes 6.50 [95% CI:5.05-8.37] vs. GMno 4.92 [95% CI:4.00-6.05]). CONCLUSION: While we did not observe associations between prior tubal ligation and postmenopausal circulating hormone levels, our findings support that prior hysterectomy was associated with lower circulating testosterone levels and higher levels of some estrogen metabolites, which may have implications for future hormone-related disease risks.

Temporal changes in mammographic breast density and breast cancer risk among women with benign breast disease.

INTRODUCTION: Benign breast disease (BBD) and high mammographic breast density (MBD) are prevalent and independent risk factors for invasive breast cancer. It has been suggested that temporal changes in MBD may impact future invasive breast cancer risk, but this has not been studied among women with BBD. METHODS: We undertook a nested case-control study within a cohort of 15,395 women with BBD in Kaiser Permanente Northwest (KPNW; 1970-2012, followed through mid-2015). Cases (n = 261) developed invasive breast cancer > 1 year after BBD diagnosis, whereas controls (n = 249) did not have breast cancer by the case diagnosis date. Cases and controls were individually matched on BBD diagnosis age and plan membership duration. Standardized %MBD change (per 2 years), categorized as stable/any increase (≥ 0%), minimal decrease of less than 5% or a decrease greater than or equal to 5%, was determined from baseline and follow-up mammograms. Associations between MBD change and breast cancer risk were examined using adjusted unconditional logistic regression. RESULTS: Overall, 64.5% (n = 329) of BBD patients had non-proliferative and 35.5% (n = 181) had proliferative disease with/without atypia. Women with an MBD decrease (≤ - 5%) were less likely to develop breast cancer (Odds Ratio (OR) 0.64; 95% Confidence Interval (CI) 0.38, 1.07) compared with women with minimal decreases. Associations were stronger among women ≥ 50 years at BBD diagnosis (OR 0.48; 95% CI 0.25, 0.92) and with proliferative BBD (OR 0.32; 95% CI 0.11, 0.99). DISCUSSION: Assessment of temporal MBD changes may inform risk monitoring among women with BBD, and strategies to actively reduce MBD may help decrease future breast cancer risk.

Short-term changes in ultrasound tomography measures of breast density and treatment-associated endocrine symptoms after tamoxifen therapy.

Although breast density decline with tamoxifen therapy is associated with greater therapeutic benefit, limited data suggest that endocrine symptoms may also be associated with improved breast cancer outcomes. However, it is unknown whether endocrine symptoms are associated with reductions in breast density after tamoxifen initiation. We evaluated treatment-associated endocrine symptoms and breast density change among 74 women prescribed tamoxifen in a 12-month longitudinal study. Treatment-associated endocrine symptoms and sound speed measures of breast density, assessed via novel whole breast ultrasound tomography (m/s), were ascertained before tamoxifen (T0) and at 1-3 (T1), 4-6 (T2), and 12 months (T3) after initiation. CYP2D6 status was genotyped, and tamoxifen metabolites were measured at T3. Using multivariable linear regression, we estimated mean change in breast density by treatment-associated endocrine symptoms adjusting for age, race, menopausal status, body mass index, and baseline density. Significant breast density declines were observed in women with treatment-associated endocrine symptoms (mean change (95% confidence interval) at T1:-0.26 m/s (-2.17,1.65); T2:-2.12 m/s (-4.02,-0.22); T3:-3.73 m/s (-5.82,-1.63); p-trend = 0.004), but not among women without symptoms (p-trend = 0.18) (p-interaction = 0.02). Similar declines were observed with increasing symptom frequency (p-trends for no symptoms = 0.91; low/moderate symptoms = 0.03; high symptoms = 0.004). Density declines remained among women with detectable tamoxifen metabolites or intermediate/efficient CYP2D6 metabolizer status. Emergent/worsening endocrine symptoms are associated with significant, early declines in breast density after tamoxifen initiation. Further studies are needed to assess whether these observations predict clinical outcomes. If confirmed, endocrine symptoms may be a proxy for tamoxifen response and useful for patients and providers to encourage adherence.

Glyphosate in house dust and risk of childhood acute lymphoblastic leukemia in California.

BACKGROUND: Residential use of pesticides has been associated with increased risk of childhood acute lymphoblastic leukemia (ALL). We evaluated determinants of glyphosate concentrations in house dust and estimated ALL risk in the California Childhood Leukemia Study (CCLS). METHODS: The CCLS is a population-based case-control study of childhood leukemia in California. Among those < 8-years (no move since diagnosis/reference date), we collected dust (2001-2007) from the room where the child spent the most time while awake and measured > 40 pesticides. Three-to-eight years later, we collected a second sample from non-movers. We used Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry to measure glyphosate (µg/g dust) for 181 ALL cases and 225 controls and for 45 households with a second dust sample. We used multivariable Tobit regression to evaluate determinants of glyphosate concentrations. Odds ratios (ORs) and 95 % confidence intervals (CI) were calculated for ALL and quartiles of the concentration (first samples) using unconditional logistic regression. We computed the within- and between-home variance and intraclass correlation coefficient (ICC). RESULTS: Glyphosate was frequently detected (cases: 98 %; controls: 99 %). Higher concentrations were associated with occupational pesticide exposure, nearby agricultural use, treatment for lawn weeds and bees/wasps, and sampling season. Increasing concentrations were not associated with ALL risk (adjusted ORQ4vsQ1 = 0.8, CI: 0.4-1.4). We observed similar null associations for boys and girls, Hispanics and non-Hispanic whites, and among those who resided in their home since birth (76 cases/117 controls) or age two (130 cases/176 controls). The ICC was 0.32 indicating high within-home temporal variability during the years of our study. CONCLUSIONS: We observed higher concentrations in homes associated with expected predictors of exposure but no association with childhood ALL risk. Due to continuing use, potential exposure to young children is high. It will be important to evaluate risk in future studies with multiple dust measurements or biomarkers of exposure.

Relation of circulating estrogens with hair relaxer and skin lightener use among postmenopausal women in Ghana.

BACKGROUND: Hair relaxers and skin lighteners have been commonly used by African women, with suggestions that they may have hormonal activity. OBJECTIVES: To investigate the relationship of hair relaxer and skin lightener use to serum estrogen/estrogen metabolite levels. METHODS: We utilized the postmenopausal population-based controls of the Ghana Breast Health Study to estimate adjusted geometric means (GM) and 95% confidence intervals of individual circulating estrogen levels by hair relaxer/skin lightener exposure categories. RESULTS: Of the 585 postmenopausal women included in our analysis, 80.2% reported hair relaxer use and 29.4% skin lightener use. Ever hair relaxer use was positively associated with estriol (adjusted GM 95.4 pmol/L vs. never 74.5, p value = 0.02) and 16-epiestriol (20.4 vs. 16.8, p value = 0.05) particularly among users of lye-based hair relaxers. Positive associations between scalp burns and unconjugated estrogens were observed (e.g., unconjugated estrone: 5+ scalp burns 76.9 [59.6-99.2] vs. no burns 64.0 [53.7-76.3], p-trend = 0.03). No association was observed between use of skin lighteners and circulating estrogens. SIGNIFICANCE: This study presents evidence that circulating 16-pathway estrogens (i.e., estriol and 16-epiestriol) may be increased in users of lye-based hair relaxer products. Among hair relaxer users, unconjugated estrogen levels were elevated in women with a greater number of scalp burns. IMPACT STATEMENT: In this population-based study of hair relaxer and skin lightener use among postmenopausal women in Ghana, altered estrogen metabolism was observed with hair relaxer use, particularly among women using lye-based products or with a greater number of scalp burns. In contrast, skin lightener use was not associated with differences in estrogen metabolism in this population. Continued investigation of the potential biological impact on breast cancer risk of hair relaxer use is warranted.

A prospective investigation of serum bile acids with risk of liver cancer, fatal liver disease, and biliary tract cancer.

Bile acids (BAs), major regulators of the gut microbiota, may play an important role in hepatobiliary cancer etiology. However, few epidemiologic studies have comprehensively examined associations between BAs and liver or biliary tract cancer. In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study, we designed 1:1 matched, nested, case-control studies of primary liver cancer (n = 201 cases), fatal liver disease (n = 261 cases), and primary biliary tract cancer (n = 138 cases). Using baseline serum collected ≤30 years before diagnosis or death, we measured concentrations of 15 BAs with liquid chromatography-tandem mass spectrometry. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable conditional logistic regression models, adjusted for age, education, diabetes status, smoking, alcohol intake, and body mass index. We accounted for multiple comparisons using a false discovery rate (FDR) correction. Comparing the highest to the lowest quartile, seven BAs were positively associated with liver cancer risk, including taurocholic acid (TCA) (OR, 5.62; 95% CI, 2.74-11.52; Q trend < 0.0001), taurochenodeoxycholic acid (TCDCA) (OR, 4.77; 95% CI, 2.26-10.08; Q trend < 0.0001), and glycocholic acid (GCA) OR, 5.30; 95% CI, 2.41-11.66; Q trend < 0.0001), and 11 were positively associated with fatal liver disease risk, including TCDCA (OR, 9.65; 95% CI, 4.41-21.14; Q trend < 0.0001), TCA (OR, 7.45; 95% CI, 3.70-14.97; Q trend < 0.0001), and GCA (OR, 6.98; 95% CI, 3.32-14.68; Q trend < 0.0001). For biliary tract cancer, associations were generally >1 but not significant after FDR correction. Conjugated BAs were strongly associated with increased risk of liver cancer and fatal liver disease, suggesting mechanistic links between BA metabolism and liver cancer or death from liver disease.

Prospective Associations of Circulating Bile Acids and Short-Chain Fatty Acids With Incident Colorectal Cancer.

BACKGROUND: Human studies investigating the prospective relationship between microbial metabolites and colorectal cancer (CRC) risk are lacking. We tested whether higher serum bile acids (BAs) and lower short-chain fatty acids (SCFAs) were associated with CRC risk. METHODS: In baseline serum collected more than 30 years before a CRC diagnosis, we quantified concentrations of 15 BAs and 6 SCFAs using targeted liquid chromatography with tandem mass spectrometry  assays in 1:1 matched cases and controls from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (men: n = 262 cases; women: n = 233 cases) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (men: n = 598 cases). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for BA and SCFA quartiles and summary measures with CRC overall and by anatomic location using multivariable conditional logistic regression models. PLCO analyses were stratified by sex. All statistical tests were 2-sided. RESULTS: In PLCO women, 7 BAs were strongly associated with increased CRC risk, including the secondary BAs, deoxycholic (ORQ4 v Q1 = 2.85, 95% CI = 1.45 to 5.60, Qtrend = 0.011), glycodeoxycholic (OR Q4 v Q1 = 3.45, 95% CI = 1.79 to 6.64, Qtrend = 0.006), taurodeoxycholic (OR Q4 v Q1 = 2.36, 95% CI = 1.22 to 4.55, Qtrend = 0.023), and glycolithocholic acid (ORQ4 v Q1 = 2.71, 95% CI = 1.41 to 5.22, Qtrend = 0.015). Women in the highest compared with lowest quartile of total SCFAs had a 45% lower risk of CRC (OR = 0.55, 95% CI = 0.31 to 0.98, Ptrend = .03). Associations for total BAs and SCFAs were strongest among women with proximal colon cancer. No statistically significant associations were observed for BA or SCFA measures among men. CONCLUSIONS: Serum concentrations of BAs, particularly downstream microbial metabolites of cholic acid, were strongly associated with increased risk of CRC among women.

Effect of risk-reducing salpingo-oophorectomy on sex steroid hormone serum levels among postmenopausal women: an NRG Oncology/Gynecologic Oncology Group study.

BACKGROUND: Risk-reducing salpingo-oophorectomy is an effective ovarian cancer risk reduction strategy. However, bilateral oophorectomy has also been associated with increased long-term nonneoplastic sequelae, effects suggested to be mediated through reductions in systemic sex steroid hormone levels. Currently, it is unclear whether the postmenopausal ovary contributes to the systemic hormonal milieu or whether postmenopausal ovarian volume or other factors, such as body mass index and age, affect systemic hormone levels. OBJECTIVE: We examined the impact of oophorectomy on sex steroid hormone levels in postmenopausal women. Furthermore, we explored how well ovarian volume measured by transvaginal ultrasound correlated with direct ovarian measures obtained during surgical pathology evaluation and investigated the association between hormone levels and ovarian volumes. STUDY DESIGN: Postmenopausal women who underwent risk-reducing salpingo-oophorectomy (180 cases) or ovarian cancer screening (38 controls) enrolled in an international, prospective study of risk-reducing salpingo-oophorectomy and risk of ovarian cancer algorithm-based screening among women at increased risk of ovarian cancer (Gynecologic Oncology Group-0199) were included in this analysis. Controls were frequency matched to the cases on age at menopause, age at study entry, and time interval between blood draws. Ovarian volume was calculated using measurements obtained from transvaginal ultrasound in both cases and controls and measurements recorded in surgical pathology reports from cases. Serum hormone levels of testosterone, androstenedione, androstenediol, dihydrotestosterone, androsterone, dehydroepiandrosterone, estrone, estradiol, and sex hormone-binding globulin were measured at baseline and follow-up. Spearman correlation coefficients were used to compare ovarian volumes as measured on transvaginal ultrasound and pathology examinations. Correlations between ovarian volumes by transvaginal ultrasound and measured hormone levels were examined using linear regression models. All models were adjusted for age. Paired t tests were performed to evaluate individual differences in hormone levels before and after risk-reducing salpingo-oophorectomy. RESULTS: Ovarian volumes measured by transvaginal ultrasound were only moderately correlated with those reported on pathology reports (Spearman rho [ρ]=0.42). The median time interval between risk-reducing salpingo-oophorectomy and follow-up for the cases was 13.3 months (range, 6.0-19.3), and the median time interval between baseline and follow-up for the controls was 12.7 months (range, 8.7-13.4). Sex steroid levels decreased with age but were not correlated with transvaginal ultrasound ovarian volume, body mass index, or time since menopause. Estradiol levels were significantly lower after risk-reducing salpingo-oophorectomy (percentage change, -61.9 post-risk-reducing salpingo-oophorectomy vs +15.2 in controls; P=.02), but no significant differences were seen for the other hormones. CONCLUSION: Ovarian volumes measured by transvaginal ultrasound were moderately correlated with volumes directly measured on pathology specimens and were not correlated with sex steroid hormone levels in postmenopausal women. Estradiol was the only hormone that declined significantly after risk-reducing salpingo-oophorectomy. Thus, it remains unclear whether the limited post-risk-reducing salpingo-oophorectomy changes in sex steroid hormones among postmenopausal women impact long-term adverse outcomes.

linc-20 and linc-9 do not have compensatory fertility roles in C. elegans.

Long intergenic non-coding RNAs (lincRNAs) are transcripts longer than 200 nucleotides which are transcribed from regions that do not overlap with protein coding sequences. Reproductive organs express high levels of lincRNAs, yet removal of many lincRNA genes with high and dynamic germline expression did not lead to fertility defects. It was previously suggested this stems from redundant roles of different lincRNA genes. We previously reported engineering C. elegans strains in which we deleted lincRNA genes with high and dynamic expression in the gonad. The individual mutations did not lead to major effects on fertility. Two of those lincRNA genes, linc-9 and linc-20, are highly homologous, suggesting they could perform redundant roles. Here we report that in the double mutant linc-9; linc-20 the brood size and embryonic lethality do not significantly differ from wild-type worms. This could be explained by either lack of fertility roles, or redundancy with other lincRNA genes.

Measured body size and serum estrogen metabolism in postmenopausal women: the Ghana Breast Health Study.

BACKGROUND: Several anthropometric measures have been associated with hormone-related cancers, and it has been shown that estrogen metabolism in postmenopausal women plays an important role in these relationships. However, little is known about circulating estrogen levels in African women, and the relevance to breast cancer or breast cancer risk factors. To shed further light on the relationship of anthropometric factors and estrogen levels in African women, we examined whether measured body mass index (BMI), waist-to-hip ratio (WHR), height, and self-reported body size were associated with serum estrogens/estrogen metabolites in a cross-sectional analysis among postmenopausal population-based controls of the Ghana Breast Health Study. METHODS: Fifteen estrogens/estrogen metabolites were quantified using liquid chromatography-tandem mass spectrometry in serum samples collected from postmenopausal female controls enrolled in the Ghana Breast Health Study, a population-based case-control study conducted in Accra and Kumasi. Geometric means (GMs) of estrogens/estrogen metabolites were estimated using linear regression, adjusting for potential confounders. RESULTS: Measured BMI (≥ 30 vs. 18.5-24.9 kg/m2) was positively associated with parent estrogens (multivariable adjusted GM for unconjugated estrone: 78.90 (66.57-93.53) vs. 50.89 (43.47-59.59), p-value < 0.0001; and unconjugated estradiol: 27.83 (21.47-36.07) vs. 13.26 (10.37-16.95), p-value < 0.0001). Independent of unconjugated estradiol, measured BMI was associated with lower levels of 2-pathway metabolites and higher levels of 16-ketoestradriol. Similar patterns of association were found with WHR; however, the associations were not entirely independent of BMI. Height was not associated with postmenopausal estrogens/estrogen metabolite levels in African women. CONCLUSIONS: We observed strong associations between measured BMI and parent estrogens and estrogen metabolite patterns that largely mirrored relations that have previously been associated with higher breast cancer risk in postmenopausal White women. The consistency of the BMI-estrogen metabolism associations in our study with those previously noted among White women suggests that estrogens likely explain part of the BMI-postmenopausal breast cancer risk in both groups. These findings merit evaluation in Black women, including prospective studies.

Platelet Activation and Reactivity in a Large Cohort of Patients with Gaucher Disease.

OBJECTIVES: Patients with Gaucher disease (GD) are at increased risk of bleeding and have varying degrees of thrombocytopenia, making the analysis of platelet function difficult. This study aimed to provide a clinically relevant quantitative assessment of platelet function and determine its relationship with bleeding and GD-related data. METHODS: Unstimulated and stimulated platelet function was measured by whole blood flow cytometry of platelet surface-activated αIIbß3 integrin (detected with monoclonal antibody PAC1), P-selectin (CD62P), and lysosomal-associated membrane protein (LAMP3/CD63) in 149 GD patients. RESULTS: GD patients had a higher level of unstimulated CD63 expression than healthy subjects, which was mildly correlated with glucosylsphingosine (lyso-Gb1) levels (r = 0.17, p-value = 0.042). Splenectomized GD patients had a higher level of unstimulated αIIbß3 integrin and P-selectin expression. Reduced platelet reactivity (-2 standard deviation of reference range) was found in 79 (53%, 95% confidence interval [CI]: 44-61%) patients, of whom 10 (6.7%, 95% CI: 3.3-12%) had more severe platelet dysfunction. In a multivariate model, only lyso-Gb1 levels were associated with the more severe platelet dysfunction. Fifty-four (49%) of 128 adult patients who completed the bleeding tendency questionnaire reported positive bleeding history. In a multivariate logistic model, older age (odds ratio [OR]: 1.05, 95% CI: 1.01-1.1) and low P-selectin reactivity (OR: 2.03, 95% CI: 1.25-3.35) were associated with more than one bleeding manifestation. CONCLUSION: Flow cytometry enables the study of platelet function in thrombocytopenic GD patients. A platelet degranulation defect, but not αIIbß3 integrin activation defect, is associated with clinical bleeding. In vivo increased CD63 expression may be related to GD-related inflammation.

Association of Endogenous Pregnenolone, Progesterone, and Related Metabolites with Risk of Endometrial and Ovarian Cancers in Postmenopausal Women: The B∼FIT Cohort.

BACKGROUND: Postmenopausal pregnenolone and/or progesterone levels in relation to endometrial and ovarian cancer risks have been infrequently evaluated. To address this, we utilized a sensitive and reliable assay to quantify prediagnostic levels of seven markers related to endogenous hormone metabolism. METHODS: Hormones were quantified in baseline serum collected from postmenopausal women in a cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (B∼FIT). Women using exogenous hormones at baseline (1992-1993) were excluded. Incident endometrial (n = 65) and ovarian (n = 67) cancers were diagnosed during 12 follow-up years and compared with a subcohort of 345 women (no hysterectomy) and 413 women (no oophorectomy), respectively. Cox models with robust variance were used to estimate cancer risk. RESULTS: Circulating progesterone levels were not associated with endometrial [tertile (T)3 vs. T1 HR (95% confidence interval): 1.87 (0.85-4.11); P trend = 0.17] or ovarian cancer risk [1.16 (0.58-2.33); 0.73]. Increasing levels of the progesterone-to-estradiol ratio were inversely associated with endometrial cancer risk [T3 vs. T1: 0.29 (0.09-0.95); 0.03]. Increasing levels of 17-hydroxypregnenolone were inversely associated with endometrial cancer risk [0.40 (0.18-0.91); 0.03] and positively associated with ovarian cancer risk [3.11 (1.39-6.93); 0.01]. CONCLUSIONS: Using sensitive and reliable assays, this study provides novel data that endogenous progesterone levels are not strongly associated with incident endometrial or ovarian cancer risks. 17-hydroxypregnenolone was positively associated with ovarian cancer and inversely associated with endometrial cancer. IMPACT: While our results require replication in large studies, they provide further support of the hormonal etiology of endometrial and ovarian cancers.

Bisection of the X chromosome disrupts the initiation of chromosome silencing during meiosis in Caenorhabditis elegans.

During meiosis, gene expression is silenced in aberrantly unsynapsed chromatin and in heterogametic sex chromosomes. Initiation of sex chromosome silencing is disrupted in meiocytes with sex chromosome-autosome translocations. To determine whether this is due to aberrant synapsis or loss of continuity of sex chromosomes, we engineered Caenorhabditis elegans nematodes with non-translocated, bisected X chromosomes. In early meiocytes of mutant males and hermaphrodites, X segments are enriched with euchromatin assembly markers and active RNA polymerase II staining, indicating active transcription. Analysis of RNA-seq data showed that genes from the X chromosome are upregulated in gonads of mutant worms. Contrary to previous models, which predicted that any unsynapsed chromatin is silenced during meiosis, our data indicate that unsynapsed X segments are transcribed. Therefore, our results suggest that sex chromosome chromatin has a unique character that facilitates its meiotic expression when its continuity is lost, regardless of whether or not it is synapsed.

Breast Cancer Risk Factors and Circulating Anti-Müllerian Hormone Concentration in Healthy Premenopausal Women.

CONTEXT: We previously reported that anti-Müllerian hormone (AMH), a marker of ovarian reserve, is positively associated with breast cancer risk, consistent with other studies. OBJECTIVE: This study assessed whether risk factors for breast cancer are correlates of AMH concentration. METHODS: This cross-sectional study included 3831 healthy premenopausal women (aged 21-57, 87% aged 35-49) from 10 cohort studies among the general population. RESULTS: Adjusting for age and cohort, AMH positively associated with age at menarche (P < 0.0001) and parity (P = 0.0008) and inversely associated with hysterectomy/partial oophorectomy (P = 0.0008). Compared with women of normal weight, AMH was lower (relative geometric mean difference 27%, P < 0.0001) among women who were obese. Current oral contraceptive (OC) use and current/former smoking were associated with lower AMH concentration than never use (40% and 12% lower, respectively, P < 0.0001). We observed higher AMH concentrations among women who had had a benign breast biopsy (15% higher, P = 0.03), a surrogate for benign breast disease, an association that has not been reported. In analyses stratified by age (<40 vs ≥40), associations of AMH with body mass index and OCs were similar in younger and older women, while associations with the other factors (menarche, parity, hysterectomy/partial oophorectomy, smoking, and benign breast biopsy) were limited to women ≥40 (P-interaction < 0.05). CONCLUSION: This is the largest study of AMH and breast cancer risk factors among women from the general population (not presenting with infertility), and it suggests that most associations are limited to women over 40, who are approaching menopause and whose AMH concentration is declining.

Oocyte aging is controlled by mitogen-activated protein kinase signaling.

Oogenesis is one of the first processes to fail during aging. In women, most oocytes cannot successfully complete meiotic divisions already during the fourth decade of life. Studies of the nematode Caenorhabditis elegans have uncovered conserved genetic pathways that control lifespan, but our knowledge regarding reproductive aging in worms and humans is limited. Specifically, little is known about germline internal signals that dictate the oogonial biological clock. Here, we report a thorough characterization of the changes in the worm germline during aging. We found that shortly after ovulation halts, germline proliferation declines, while apoptosis continues, leading to a gradual reduction in germ cell numbers. In late aging stages, we observed that meiotic progression is disturbed and crossover designation and DNA double-strand break repair decrease. In addition, we detected a decline in the quality of mature oocytes during aging, as reflected by decreasing size and elongation of interhomolog distance, a phenotype also observed in human oocytes. Many of these altered processes were previously attributed to MAPK signaling variations in young worms. In support of this, we observed changes in activation dynamics of MPK-1 during aging. We therefore tested the hypothesis that MAPK controls oocyte quality in aged worms using both genetic and pharmacological tools. We found that in mutants with high levels of activated MPK-1, oocyte quality deteriorates more rapidly than in wild-type worms, whereas reduction of MPK-1 levels enhances quality. Thus, our data suggest that MAPK signaling controls germline aging and could be used to attenuate the rate of oogenesis quality decline.

Relation of Quantitative Histologic and Radiologic Breast Tissue Composition Metrics With Invasive Breast Cancer Risk.

Background: Benign breast disease (BBD) is a strong breast cancer risk factor, but identifying patients that might develop invasive breast cancer remains a challenge. Methods: By applying machine-learning to digitized hematoxylin and eosin-stained biopsies and computer-assisted thresholding to mammograms obtained circa BBD diagnosis, we generated quantitative tissue composition metrics and determined their association with future invasive breast cancer diagnosis. Archival breast biopsies and mammograms were obtained for women (18-86 years of age) in a case-control study, nested within a cohort of 15 395 BBD patients from Kaiser Permanente Northwest (1970-2012), followed through mid-2015. Patients who developed incident invasive breast cancer (ie, cases; n = 514) and those who did not (ie, controls; n = 514) were matched on BBD diagnosis age and plan membership duration. All statistical tests were 2-sided. Results: Increasing epithelial area on the BBD biopsy was associated with increasing breast cancer risk (odds ratio [OR]Q4 vs Q1 = 1.85, 95% confidence interval [CI] = 1.13 to 3.04; P trend = .02). Conversely, increasing stroma was associated with decreased risk in nonproliferative, but not proliferative, BBD (P heterogeneity = .002). Increasing epithelium-to-stroma proportion (ORQ4 vs Q1 = 2.06, 95% CI =1.28 to 3.33; P trend = .002) and percent mammographic density (MBD) (ORQ4 vs Q1 = 2.20, 95% CI = 1.20 to 4.03; P trend = .01) were independently and strongly predictive of increased breast cancer risk. In combination, women with high epithelium-to-stroma proportion and high MBD had substantially higher risk than those with low epithelium-to-stroma proportion and low MBD (OR = 2.27, 95% CI = 1.27 to 4.06; P trend = .005), particularly among women with nonproliferative (P trend = .01) vs proliferative (P trend = .33) BBD. Conclusion: Among BBD patients, increasing epithelium-to-stroma proportion on BBD biopsies and percent MBD at BBD diagnosis were independently and jointly associated with increasing breast cancer risk. These findings were particularly striking for women with nonproliferative disease (comprising approximately 70% of all BBD patients), for whom relevant predictive biomarkers are lacking.

Endogenous Progestogens and Colorectal Cancer Risk among Postmenopausal Women.

BACKGROUND: The role of progestogens in colorectal cancer development is poorly characterized. To address this, our group developed a highly sensitive assay to measure concentrations of seven markers of endogenous progestogen metabolism among postmenopausal women. METHODS: The markers were measured in baseline serum collected from postmenopausal women in a case-cohort study within the breast and bone follow-up to the fracture intervention trial (B∼FIT). We followed women not using exogenous hormones at baseline (1992-1993) for up to 12 years: 187 women with incident colorectal cancer diagnosed during follow-up and a subcohort of 495 women selected on strata of age and clinical center. We used adjusted Cox regression models with robust variance to estimate risk for colorectal cancer [hazard ratios (HR), 95% confidence intervals (CI)]. RESULTS: High concentrations of pregnenolone and progesterone were not associated with colorectal cancer [quintile(Q)5 versus Q1: pregnenolone HR, 0.71, 95% CI, 0.40-1.25; progesterone HR, 1.25; 95% CI, 0.71-2.22]. A trend of increasing risk was suggested, but statistically imprecise across quintiles of 17-hydroxypregnenolone (Q2 to Q5 HRs, 0.75-1.44; P trend, 0.06). CONCLUSIONS: We used sensitive and reliable assays to measure multiple circulating markers of progestogen metabolism. Progestogens were generally unassociated with colorectal cancer risk in postmenopausal women. IMPACT: Our findings are consistent with most prior research on circulating endogenous sex hormones, which taken together suggest that sex hormones may not be major drivers of colorectal carcinogenesis in postmenopausal women.

Risk factors for breast cancer development by tumor characteristics among women with benign breast disease.

BACKGROUND: Among women diagnosed with invasive breast cancer, 30% have a prior diagnosis of benign breast disease (BBD). Thus, it is important to identify factors among BBD patients that elevate invasive cancer risk. In the general population, risk factors differ in their associations by clinical pathologic features; however, whether women with BBD show etiologic heterogeneity in the types of breast cancers they develop remains unknown. METHODS: Using a nested case-control study of BBD and breast cancer risk conducted in a community healthcare plan (Kaiser Permanente Northwest), we assessed relationships of histologic features in BBD biopsies and patient characteristics with subsequent breast cancer risk and tested for heterogeneity of associations by estrogen receptor (ER) status, tumor grade, and size. The study included 514 invasive breast cancer cases (median follow-up of 9 years post-BBD diagnosis) and 514 matched controls, diagnosed with proliferative or non-proliferative BBD between 1971 and 2006, with follow-up through mid-2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using multivariable polytomous logistic regression models. RESULTS: Breast cancers were predominantly ER-positive (86%), well or moderately differentiated (73%), small (74% < 20 mm), and stage I/II (91%). Compared to patients with non-proliferative BBD, proliferative BBD with atypia conferred increased risk for ER-positive cancer (OR = 5.48, 95% CI = 2.14-14.01) with only one ER-negative case, P-heterogeneity = 0.45. The presence of columnar cell lesions (CCLs) at BBD diagnosis was associated with a 1.5-fold increase in the risk of both ER-positive and ER-negative tumors, with a 2-fold increase (95% CI = 1.21-3.58) observed among postmenopausal women (56%), independent of proliferative BBD status with and without atypia. We did not identify statistically significant differences in risk factor associations by tumor grade or size. CONCLUSION: Most tumors that developed after a BBD diagnosis in this cohort were highly treatable low-stage ER-positive tumors. CCL in BBD biopsies may be associated with moderately increased risk, independent of BBD histology, and irrespective of ER status.