Evidence suggests that the hormonal milieu of pregnancy is an important determinant of subsequent cancer and other chronic diseases in both the mother and the offspring. Many of the existing ...maternity and birth cohorts include specimens drawn only once during pregnancy. How well a single blood specimen collected during a pregnancy characterizes exposure to these hormones throughout gestation, and also in subsequent pregnancies, is not well understood.
We used serial serum samples from 71 pregnant women (25 primiparous, 25 multiparous, and 21 with two consecutive pregnancies) with natural, complication-free pregnancies and a healthy offspring at term who participated in a population-based screening trial for congenital infections in Finland between January 1st, 1988 and June 30, 1989 and provided a blood sample in each trimester.
Hormone levels were more strongly correlated between consecutive trimesters of a pregnancy than between the 1st and 3rd trimester (e.g., estradiol, rT1 vs. T2 = 0.51 and rT2 vs. T3 = 0.60, p < 0.01; rT1 vs. T3 = 0.32, p < 0.05). Concentrations of sRANKL remained stable throughout gestation, whereas estradiol, estrone, progesterone, testosterone, prolactin, and osteoprotegerin increased throughout pregnancy. First trimester hormone concentrations explained less of the variation in the third trimester on their own than second trimester hormone levels (e.g. estradiol R(2) T1 = 16 % and R(2) T2 = 42 %). Addition of maternal (e.g., smoking) and/or child characteristics (e.g., sex) improved the accuracy of the 3rd trimester estimates for some of the hormones.
One hormone measurement in early pregnancy, in conjunction with maternal and fetal characteristics, permits estimation of 3rd trimester hormone concentrations. Therefore, single hormone measurements available from maternity cohorts are suitable to quantify hormone exposure during pregnancy. To our knowledge, we provide the first data on correlations between hormone concentrations both across trimesters of a single pregnancy, as well as between two subsequent pregnancies.
Objective To identify reproductive, lifestyle, hormonal, and other correlates of circulating antimüllerian hormone (AMH) concentrations in mostly late premenopausal women. Design Cross-sectional ...study. Setting Not applicable. Patient(s) A total of 671 premenopausal women not known to have cancer. Intervention(s) None. Main Outcome Measure(s) Concentrations of AMH were measured in a single laboratory using the picoAMH ELISA. Multivariable-adjusted median (and interquartile range) AMH concentrations were calculated using quantile regression for several potential correlates. Result(s) Older women had significantly lower AMH concentrations (≥40 n = 444 vs. <35 years n = 64, multivariable-adjusted median 0.73 ng/mL vs. 2.52 ng/mL). Concentrations of AMH were also significantly lower among women with earlier age at menarche (<12 n = 96 vs. ≥14 years n = 200: 0.90 ng/mL vs. 1.12 ng/mL) and among current users of oral contraceptives (n = 27) compared with never or former users (n = 468) (0.36 ng/mL vs. 1.15 ng/mL). Race, body mass index, education, height, smoking status, parity, and menstrual cycle phase were not significantly associated with AMH concentrations. There were no significant associations between AMH concentrations and androgen or sex hormone-binding globulin concentrations or with factors related to blood collection (e.g., sample type, time, season, and year of blood collection). Conclusion(s) Among premenopausal women, lower AMH concentrations are associated with older age, a younger age at menarche, and currently using oral contraceptives, suggesting these factors are related to a lower number or decreased secretory activity of ovarian follicles.
Purpose
Oral contraceptives (OCs) have been consistently associated with a reduced ovarian cancer risk; however, most previous studies included women in older birth cohorts using high-dose OC ...formulations. We assessed OC use, including type and dose, and ovarian cancer risk among women born between 1947 and 1964 using more recent formulations.
Methods
We included 110,929 Nurses’ Health Study II participants. Women reported duration of OC use and brands used from age 13 to baseline (1989) and every 2 years thereafter through 2009. We categorized brands by estrogen and progestin type, dose, and potency, and used Cox proportional hazards models, adjusted for age, calendar time, reproductive factors, and body mass index, to assess associations with ovarian cancer.
Results
Over 2,178,679 person-years of follow-up, we confirmed 281 cases. At baseline, 83% of participants reported ever using OCs. Compared to never use, we observed an increased risk of ovarian cancer with ≤6 months of OC use (HR 1.82; 95% CI 1.13–2.93) but a non-significant 57% (95% CI 0.18–1.03) decreased risk with ≥15 years of OC use. The increased risk among short-term users (≤1 year) was restricted to OCs containing mestranol (HR 1.83; 95% CI 1.16–2.88) and first-generation progestin (HR 1.72; 95% CI 1.11–2.65).
Conclusion
The associations between OCs and ovarian cancer observed for this younger birth cohort differ substantially from the results of previous cohort studies, possibly reflecting changes in OC formulations and use patterns over time, although these results could be due to chance. Additional studies should evaluate newer OC formulations and ovarian cancer risk.
Pregnancy and parity are associated with subsequent breast cancer risk. Experimental and epidemiologic data suggest a role for pregnancy sex steroid hormones.
We conducted a nested case-control study ...in the Northern Sweden Maternity Cohort (1975-2007). Eligible women had provided a blood sample in the first 20 weeks of gestation during a primiparous pregnancy leading to a term delivery. The current study includes 223 cases and 417 matched controls (matching factors: age at and date of blood collection). Estrogen receptor (ER) and progesterone receptor (PR) status was available for all cases; androgen receptor (AR) data were available for 41% of cases (n = 92). Sex steroids were quantified by high-performance liquid chromatography tandem mass spectrometry. Odds ratios (ORs) and 95% confidence intervals were estimated using conditional logistic regression.
Higher concentrations of circulating progesterone in early pregnancy were inversely associated with ER+/PR+ breast cancer risk (OR
: 0.64 (0.41-1.00)). Higher testosterone was positively associated with ER+/PR+ disease risk (OR
: 1.57 (1.13-2.18)). Early pregnancy estrogens were not associated with risk, except for relatively high estradiol in the context of low progesterone (split at median, relative to low concentrations of both; OR: 1.87 (1.11-3.16)). None of the investigated hormones were associated with ER-/PR- disease, or with AR+ or AR+/ER+/PR+ disease.
Consistent with experimental models, high progesterone in early pregnancy was associated with lower risk of ER+/PR+ breast cancer in the mother. High circulating testosterone in early pregnancy, which likely reflects nonpregnant premenopausal exposure, was associated with higher risk of ER+/PR+ disease.
Abstract
Background: Activation of the receptor activator of nuclear factor kappa-B (RANK)-axis promotes mammary tumor development in experimental models. Circulating concentrations of soluble RANK ...ligand (sRANKL) may influence breast cancer risk via RANK activation; this may be modulated by circulating concentrations of osteoprotegerin (OPG), the decoy receptor for RANKL. sRANKL and breast cancer risk in humans have not previously been investigated.
Methods: A case-control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 1976 incident invasive breast cancer cases (estrogen receptor positive (ER+), n=1598), matched 1:1 to controls, were included in the analysis. Women were both pre- and postmenopausal at blood collection. Serum sRANKL was quantified using an enzyme-linked immunosorbent assay (ELISA). Serum OPG was quantified using an electrochemiluminescent assay. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated using conditional logistic regression.
Results: Associations between sRANKL and breast cancer risk differed by tumor hormone receptor status (phet 0.05). Higher concentrations of sRANKL were suggestively associated with risk of ER+ breast cancer (top vs. bottom quintile OR 1.36 0.99-1.87; ptrend 0.31). While results considering the sRANKL/OPG ratio were similar to those for sRANKL alone for hormone receptor positive breast cancer, we saw a suggestive inverse association between the ratio and ER-PR- disease (5th vs. 1st quintile OR 0.60 0.31-1.16; ptrend 0.04).
Conclusions: This study provides the first prospective data on sRANKL and breast cancer risk, providing suggestive evidence of a possible association between sRANKL concentrations and breast cancer. High circulating levels sRANKL in the context of low OPG may represent novel risk markers for hormone receptor positive breast cancer.
Table 1.Circulating concentrations of sRANKL and breast cancer risk by hormone-receptor subtype: EPIC nested case-control studyQuintiles12345ptrend*phet*sRANKLER+/PR+Cases/Controls167/198203/183176/192160/157214/190OR (95% CI)ref.1.32 (0.97-1.81)1.12 (0.81-1.54)1.19 (0.85-1.65)1.36 (0.99-1.87)0.310.05ER-/PR-Cases/Controls52/5157/4047/5349/5646/51OR (95% CI)ref.1.58 (0.82-3.04)0.97 (0.51-1.84)0.83 (0.44-1.58)0.74 (0.39-1.40)0.08sRANKL/OPG RatioER+/PR+Cases/Controls146/177175/181186/178184/180224/199OR (95% CI)ref.1.19 (0.85-1.65)1.25 (0.90-1.75)1.22 (0.87-1.70)1.42 (1.01-1.98)0.220.02ER-/PR-Cases/Controls45/4146/4253/4760/6046/60OR (95% CI)ref.1.11 (0.56-2.17)1.09 (0.57-2.09)0.87 (0.45-1.68)0.60 (0.31-1.16)0.04* based on continuous log2-transformed values; Conditional logistic regression models adjusted for: ages at menarche (<12, 13, 14, ≥15, missing), menopause (<44, 44-47, 48-50, 51-52, 53-54, ≥55, missing), and first full-term pregnancy (no FTP, <25, 25-30, ≥30, missing), and number of full-term pregnancies (0, 1, 2, ≥3, missing) and BMI (kg/m2, continuous).
Citation Format: Danja Sarink, Helena Schock, Theron Johnson, EPIC cohort collaborators, Rudolf Kaaks, Renee T. Fortner. The RANK-axis and breast cancer risk by hormone receptor subtype: Results from the EPIC cohort abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4959. doi:10.1158/1538-7445.AM2017-4959
Invasive epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The etiology of EOC remains elusive; however, experimental and epidemiologic data suggest a role for ...hormone-related exposures in ovarian carcinogenesis and risk factor differences by histologic phenotypes and developmental pathways. Research on prediagnosis androgen concentrations and EOC risk has yielded inconclusive results, and analyses incorporating EOC subtypes are sparse. We conducted a pooled analysis of 7 nested case-control studies in the Ovarian Cancer Cohort Consortium to investigate the association between pre-diagnosis circulating androgens testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), and EOC risk by tumor characteristics (i.e., histology, grade, and stage). The final study population included 1,331 EOC cases and 3,017 matched controls. Multivariable conditional logistic regression was used to assess risk associations in pooled individual data. Testosterone was positively associated with EOC risk (all subtypes combined, OR
= 1.12; 95% confidence interval 1.02-1.24); other endogenous androgens and SHBG were not associated with overall risk. Higher concentrations of testosterone and androstenedione associated with an increased risk in endometrioid and mucinous tumors e.g., testosterone, endometrioid tumors, OR
= 1.40 (1.03-1.91), but not serous or clear cell. An inverse association was observed between androstenedione and high grade serous tumors OR
= 0.76 (0.60-0.96). Our analyses provide further evidence for a role of hormone-related pathways in EOC risk, with differences in associations between androgens and histologic subtypes of EOC.
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OBJECTIVE:To examine the associations of maternal and child characteristics with early pregnancy maternal concentrations of testosterone, androstenedione, progesterone, 17-hydroxyprogesterone, and ...estradiol (E2).
METHODS:We analyzed these hormones among 1,343 women with singleton pregnancies who donated serum samples to the Finnish Maternity Cohort from 1986 to 2006 during the first half of pregnancy (median 11 weeks). The associations of maternal and child characteristics with hormone concentrations were investigated by correlation and multivariable regression.
RESULTS:Women older than age 30 years had lower androgen and E2 but higher progesterone concentrations than women younger than that age. Multiparous women had 14% lower testosterone, 11% lower androstenedione and 17-hydroxyprogesterone, 9% lower progesterone, and 16% lower E2 concentrations compared with nulliparous women (all P<.05). Smoking mothers had 11%, 18%, and 8% higher testosterone, androstenedione, and 17-hydroxyprogesterone levels, respectively, but 10% lower progesterone compared with nonsmoking women (all P<.05). E2 concentrations were 9% higher (P<.05) among women with a female fetus compared with those with a male fetus.
CONCLUSION:Parity, smoking, and, to a lesser extent, maternal age and child sex are associated with sex steroid levels during the first half of a singleton pregnancy. The effects of smoking on the maternal hormonal environment and the possible long-term deleterious consequences on the fetus deserve further evaluation.
LEVEL OF EVIDENCE:II
Results from prospective studies on premenopausal serum hormone levels in relation to breast cancer risk have been inconclusive, especially with regard to tumor subtypes. Using a case–control study ...nested within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (801 breast cancer cases and 1,132 matched control subjects), we analyzed the relationships of prediagnostic serum estradiol, free estradiol, progesterone, testosterone, free testosterone and sex hormone‐binding globulin (SHBG) levels with the risk of breast cancer by estrogen and progesterone receptor‐positive and ‐negative breast tumors and by age at diagnoses. Higher prediagnostic serum levels of testosterone and free testosterone were associated with an increased overall risk of breast cancer ORQ4‐Q1 = 1.56 (95% CI 1.15–2.13), ptrend = 0.02 for testosterone and ORQ4‐Q1 = 1.33 (95% CI 0.99–1.79), ptrend = 0.04 for free testosterone, but no significant risk association was observed for estradiol, free estradiol, progesterone and SHBG. Tests for heterogeneity between receptor‐positive and ‐negative tumors were not significant. When analysis were stratified by age at tumor diagnosis, the odds ratios observed for estradiol were stronger and borderline significant for breast cancer diagnosed at age less than 50 ORQ4‐Q1 = 1.32 (95% CI 0.87–2.01), ptrend = 0.05 compared to breast cancer diagnosed at age 50 or above ORQ4‐Q1 = 0.94 (95% CI 0.60–1.47), ptrend = 0.34, phet = 0.04. In conclusion, our data indicate that higher premenopausal circulating testosterone levels are associated with an increased risk of developing breast cancer, but do not show a significant association of estradiol or progesterone with breast cancer risk, overall, by menstrual cycle phase or by tumor receptor status, although a possible risk increase with higher estradiol levels for tumors diagnosed before age 50 was seen.
What's new?
Sex hormones have often been connected with the development of breast cancer, and estrogens have clear pro‐proliferative effects on breast cancer cells. In this large prospective study, the authors underscore a direct association of premenopausal levels of testosterone with subsequent breast cancer risk. By contrast, no direct relationship between premenopausal estrogen and progesterone levels with increased breast cancer risk was observed although a weak association between higher estradiol levels and increased risk for tumors diagnosed before age 50 was noted. The authors point to the possibility that a conversion from androgen to estrogen might take place in the breast that may mechanistically explain the increased risk in breast cancer development when androgens are high.
Evidence suggests an etiologic role for inflammation in ovarian carcinogenesis and heterogeneity between tumor subtypes and anthropometric indices. Prospective studies on circulating inflammatory ...markers and epithelial invasive ovarian cancer (EOC) have predominantly investigated overall risk; data characterizing risk by tumor characteristics (histology, grade, stage, dualistic model of ovarian carcinogenesis) and anthropometric indices are sparse.
We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate C-reactive protein (CRP), IL6, and EOC risk by tumor characteristics. A total of 754 eligible EOC cases were identified; two controls (n = 1,497) were matched per case. We used multivariable conditional logistic regression to assess associations.
CRP and IL6 were not associated with overall EOC risk. However, consistent with prior research, CRP >10 versus CRP ≤1 mg/L was associated with higher overall EOC risk OR, 1.67 (1.03-2.70). We did not observe significant associations or heterogeneity in analyses by tumor characteristics. In analyses stratified by waist circumference, inflammatory markers were associated with higher risk among women with higher waist circumference; no association was observed for women with normal waist circumference e.g., IL6: waist ≤80: ORlog2, 0.97 (0.81-1.16); waist >88: ORlog2, 1.78 (1.28-2.48), Pheterogeneity ≤ 0.01.
Our data suggest that high CRP is associated with increased risk of overall EOC, and that IL6 and CRP may be associated with EOC risk among women with higher adiposity.
Our data add to global evidence that ovarian carcinogenesis may be promoted by an inflammatory milieu.
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