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Human Chorionic Gonadotropin Does Not Correlate with Risk for Maternal Breast Cancer: Results from the Finnish Maternity Cohort.

ABSTRACT: Human chorionic gonadotropin (hCG) is necessary for the maintenance of early pregnancy and promotes normal breast cell differentiation. Administered hCG reduces risk of carcinogen-induced breast cancer in animal models, and higher circulating hCG concentrations were associated with significantly lower long-term risk of breast cancer in a prior nested case-control study. In this study, we investigated early-pregnancy hCG concentrations and subsequent breast cancer risk. We conducted a nested case-control study with 1,191 cases and 2,257 controls (matched on age and date at blood collection) in the Finnish Maternity Cohort, a cohort with serum samples from 98% of pregnancies registered in Finland since 1983. This study included women with a serum sample collected early (<140 days gestation) in their first pregnancy resulting in a live, term birth. Breast cancer cases were identified via the Finnish Cancer Registry. Age at breast cancer diagnosis ranged from 22 to 58 years (mean: 41 years). hCG was measured using a solid-phase competitive chemiluminescence assay. Odds ratios (OR) were calculated using conditional logistic regression. We observed no association between hCG and breast cancer risk, overall [Quartile 4 vs. 1, OR, 1.14; 95% confidence interval (CI), 0.94-1.39], by estrogen and progesterone receptor status, or by ages at first-term birth or diagnosis. Associations did not differ by time between pregnancy and diagnosis (e.g., <5 years, ORQ4 vs. Q1, 1.10; 95% CI, 0.64-1.89; ?15 years, ORQ4 vs. Q1, 1.36; 95% CI, 0.86-2.13; pheterogeneity = 0.62). This large prospective study does not support an inverse relationship between early pregnancy serum hCG concentrations and breast cancer risk. Cancer Res; 77(1); 134-41. ©2016 AACR.

SUBMITTER: Fortner RT

PROVIDER: S-EPMC5270509 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Human Chorionic Gonadotropin Does Not Correlate with Risk for Maternal Breast Cancer: Results from the Finnish Maternity Cohort.

Fortner Renée T RT Schock Helena H Kaaks Rudolf R Lehtinen Matti M Pukkala Eero E Lakso Hans-Åke HÅ Tanner Minna M Kallio Raija R Joensuu Heikki H Korpela Jaana J Toriola Adetunji T AT Hallmans Göran G Grankvist Kjell K Zeleniuch-Jacquotte Anne A Toniolo Paolo P Lundin Eva E Surcel Heljä-Marja HM

Cancer research 20161026 1

Human chorionic gonadotropin (hCG) is necessary for the maintenance of early pregnancy and promotes normal breast cell differentiation. Administered hCG reduces risk of carcinogen-induced breast cancer in animal models, and higher circulating hCG concentrations were associated with significantly lower long-term risk of breast cancer in a prior nested case-control study. In this study, we investigated early-pregnancy hCG concentrations and subsequent breast cancer risk. We conducted a nested case ...[more]

PMID: 27784743

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Project description:OBJECTIVES:Abnormal placentation in early pregnancy may play a role in the pathogenesis of pre-eclampsia. Human chorionic gonadotropin (hCG) regulates placental development and angiogenesis and may affect the ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in the serum. The aims of this study were to investigate the association of total hCG with the risk of pre-eclampsia and to examine the potential effect of pro- and anti-angiogenic factors on this association. METHODS:This was a population-based prospective cohort study of 7754 women with a singleton pregnancy. Total hCG was measured in the first available sample (median gestational age, 14.4 weeks; 95% range, 10.1-26.1 weeks) and sFlt-1 and PlGF concentrations in early (< 18 weeks; median, 13.2 weeks; 95% range, 9.6-17.6 weeks) and in mid- (18-25 weeks; median, 20.4 weeks; 95% range, 18.5-23.5 weeks) pregnancy. We tested the association of hCG concentration and risk of pre-eclampsia using regression analysis, adjusting for maternal age, ethnicity, body mass index, parity, education level, smoking status and fetal sex. Additionally, we assessed whether this association was affected by the sFlt-1/PlGF ratio. RESULTS:High hCG concentration was associated with a 1.5-2.7-fold increased risk of pre-eclampsia (P = 0.0001), depending on the cut-off used, and with increased sFlt-1/PlGF ratio during early pregnancy (P < 0.0001). The association between high hCG and pre-eclampsia attenuated by roughly 40% after adjustment for early-pregnancy sFlt-1/PlGF ratio (β-estimate change from 0.19 ± 0.10 (P = 0.052) to 0.12 ± 0.10 (P = 0.22)). CONCLUSIONS:High total hCG concentration in early pregnancy is associated with an increased risk of pre-eclampsia. The effect of high hCG concentration on the balance between pro- and anti-angiogenic factors during pregnancy may have a role in the pathophysiology of pre-eclampsia. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Project description:BackgroundThe proportion of hyperglycosylated human chorionic gonadotropin (hCG-h) to total human chorionic gonadotropin (%hCG-h) during the first trimester is a promising biomarker for prediction of early-onset pre-eclampsia. We wanted to evaluate the performance of clinical risk factors, mean arterial pressure (MAP), %hCG-h, hCGβ, pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF) and mean pulsatility index of the uterine artery (Uta-PI) in the first trimester in predicting pre-eclampsia (PE) and its subtypes early-onset, late-onset, severe and non-severe PE in a high-risk cohort.MethodsWe studied a subcohort of 257 high-risk women in the prospectively collected Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) cohort. Multivariate logistic regression was used to construct the prediction models. The first model included background variables and MAP. Additionally, biomarkers were included in the second model and mean Uta-PI was included in the third model. All variables that improved the model fit were included at each step. The area under the curve (AUC) was determined for all models.ResultsWe found that lower levels of serum PlGF concentration were associated with early-onset PE, whereas lower %hCG-h was associated with the late-onset PE. Serum PlGF was lower and hCGβ higher in severe PE, while %hCG-h and serum PAPP-A were lower in non-severe PE. By using multivariate regression analyses the best prediction for all PE was achieved with the third model: AUC was 0.66, and sensitivity 36% at 90% specificity. Third model also gave the highest prediction accuracy for late-onset, severe and non-severe PE: AUC 0.66 with 32% sensitivity, AUC 0.65, 24% sensitivity and AUC 0.60, 22% sensitivity at 90% specificity, respectively. The best prediction for early-onset PE was achieved using the second model: AUC 0.68 and 20% sensitivity at 90% specificity.ConclusionsAlthough the multivariate models did not meet the requirements to be clinically useful screening tools, our results indicate that the biomarker profile in women with risk factors for PE is different according to the subtype of PE. The heterogeneous nature of PE results in difficulty to find new, clinically useful biomarkers for prediction of PE in early pregnancy in high-risk cohorts.Trial registrationInternational Standard Randomised Controlled Trial number ISRCTN14030412 , Date of registration 6/09/2007, retrospectively registered.

Project description:Immunopathological outcomes in Systemic Lupus Erythematosus (SLE; or lupus) are believed to be autoantibody-mediated. Conditions which promote a Th2 skew (such as pregnancy) should encourage antibody production, worsening antibody-mediated diseases while ameliorating Th1/Th17-mediated diseases. Although an increased propensity toward autoreactivity can be observed in pregnant lupus patients and in pregnant lupus-prone mice, whether a unique human pregnancy-specific factor can contribute to such effects is unknown. This study assessed whether human chorionic gonadotropin (hCG, a pregnancy-specific hormone of diverse function) at physiological concentrations could mediate stimulatory influences on immune parameters in non-pregnant, lupus-prone mice, in light of the hormone's ameliorating effects on Th1-mediated autoimmunity in murine models. Results demonstrate that administration of hCG heightened global autoreactivity in such mice; antibodies to dsDNA, RNP68, Protein S, Protein C, β2-glycoprotein 1, and several phospholipids were enhanced, and hormone administration had adverse effects on animal survival. Specifically in splenic cell cultures containing cells derived from lupus-prone mice, hCG demonstrated synergistic effects with TLR ligands (up-modulation of costimulatory markers on B cells) as well as with TCR stimuli (enhanced proliferative responses, enhanced levels of cytokines, and the phosphorylation of p38). In both instances, enhanced synthesis of lupus-associated cytokines was observed, in addition to the heightened generation of autoantibodies reactive toward apoptotic blebs. These results suggest that selective transducive, proliferative, and differentiative effects of hCG on adaptive immune cells may drive autoreactive responses in a lupus environment, and may also potentially provide insights into the association between the presence of higher hCG levels (or the administration of hCG) with the presence (or appearance) of humoral autoimmunity.

Project description:During histiotrophic nutrition of the embryo, maternal platelets may be the first circulating maternal cells that find their way into the placental intervillous space through narrow intertrophoblastic gaps within the plugs of spiral arteries. Activation of platelets at the maternal-fetal interface can influence trophoblast behavior and has been implicated in serious pregnancy pathologies. Here, we show that platelet-derived factors impaired expression and secretion of the human chorionic gonadotropin beta-subunit (?hCG) in human first trimester placental explants and the trophoblast cell line BeWo. Impaired ?hCG synthesis was not the consequence of hampered morphological differentiation, as assessed by analysis of differentiation-associated genes and electron microscopy. Platelet-derived factors did not affect intracellular cAMP levels and phosphorylation of CREB, but activated Smad3 and its downstream-target plasminogen activator inhibitor (PAI)-1 in forskolin-induced BeWo cell differentiation. While TGF-? type I receptor inhibitor SB431542 did not restore impaired ?hCG production in response to platelet-derived factors, Smad3 inhibitor SIS3 interfered with CREB activation, suggesting an interaction of cAMP/CREB and Smad3 signaling. Sequestration of transcription co-activators CBP/p300, known to bind both CREB and Smad3, may limit ?hCG production, since CBP/p300 inhibitor C646 significantly restricted its forskolin-induced upregulation. In conclusion, our study suggests that degranulation of maternal platelets at the early maternal-fetal interface can impair placental ?hCG production, without substantially affecting morphological and biochemical differentiation of villous trophoblasts. KEY MESSAGES: Maternal platelets can be detected on the surface of the placental villi and in intercellular gaps of trophoblast cell columns from gestational week 5 onwards. Platelet-derived factors impair hCG synthesis in human first trimester placenta. Platelet-derived factors activate Smad3 in trophoblasts. Smad3 inhibitor SIS3 interferes with forskolin-induced CREB signaling. Sequestration of CBP/p300 by activated Smad3 may limit placental hCG production.

Project description:BackgroundIndications for chemotherapy in gestational trophoblastic disease include raised human chorionic gonadotropin (hCG) concentrations 6 months after uterine evacuation of hydatidiform mole, even when values are falling. We aimed to establish whether chemotherapy is always necessary in these patients.MethodsWe retrospectively identified women registered between January, 1993, and May, 2008, at Charing Cross Hospital, London, UK, who had persistently high hCG concentrations 6 months after evacuation of hydatidiform mole. Rates of hCG normalisation, relapse, and death were assessed in patients continued under surveillance and those who received chemotherapy after 6 months. We postulated that a surveillance policy would be clinically acceptable if hCG values returned to normal in 75% of patients or more.Findings76 (<1%) of 13,960 patients with hydatidiform moles had persistently high hCG concentrations of more than 5 IU/L 6 months after evacuation. 66 (87%) patients continued under surveillance and hCG values spontaneously returned to normal without chemotherapy in 65 (98%) of these patients. Values in one patient did not become normal because of chronic renal failure, but she remains healthy. Ten patients received chemotherapy, and hCG concentrations returned to normal in eight (80%) of these individuals (surveillance vs chemotherapy groups p=0·044) and remained slightly high (6-11 IU/L) in two without any associated clinical problems off treatment. We noted no significant differences between individuals in the surveillance and chemotherapy groups, apart from lower median hCG concentrations 6 months after evacuation in those under surveillance than in those given chemotherapy (13 IU/L, range 5-887, vs 157 IU/L, range 6-6438; p=0·004). Overall, there were no deaths in this series.InterpretationA surveillance policy seems to be clinically acceptable in patients with low and declining concentrations of hCG 6 months after evacuation of hydatidiform mole.FundingNational Commissioning Group, Imperial Experimental Cancer Medicine Centre, Imperial Biomedical Research Centre, and Cancer Research UK.

Dataset Information

Human Chorionic Gonadotropin Does Not Correlate with Risk for Maternal Breast Cancer: Results from the Finnish Maternity Cohort.

Publications

Human Chorionic Gonadotropin Does Not Correlate with Risk for Maternal Breast Cancer: Results from the Finnish Maternity Cohort.

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