@article{74836b401fd44f37986de92013d0e0ca,
title = "Circulating androgens and postmenopausal ovarian cancer risk in the Women's Health Initiative Observational Study",
abstract = "Our knowledge of epidemiologic risk factors for ovarian cancer supports a role for androgens in the pathogenesis of this disease; however, few studies have examined associations between circulating androgens and ovarian cancer risk. Using highly sensitive LC–MS/MS assays, we evaluated associations between pre-diagnostic serum levels of 12 androgens, including novel androgen metabolites that reflect androgen activity in tissues, and ovarian cancer risk among postmenopausal women in a nested case–control study in the Women's Health Initiative (WHI) Observational Study (OS). We frequency-matched 169 ovarian cancer cases to 410 controls from women enrolled in WHI-OS who were not using menopausal hormones at enrollment/blood draw. We estimated associations overall and by subtype (n = 102 serous/67 non-serous) using multivariable adjusted logistic regression. Androgen/androgen metabolite levels were not associated with overall ovarian cancer risk. In analyses by subtype, women with increased levels of androsterone-glucuronide (ADT-G) and total 5-α reduced glucuronide metabolites (markers of tissue-level androgenic activity) were at increased risk of developing non-serous ovarian cancer: ADT-G tertile (T)3 versus T1 odds ratio [OR] (95% confidence interval [CI]) 4.36 (1.68–11.32), p-heterogeneity 0.002; total glucuronide metabolites 3.63 (1.47–8.95), 0.002. Risk of developing serous tumors was unrelated to these markers. ADT-G and total glucuronide metabolites, better markers of tissue-level androgenic activity in women than testosterone, were associated with an increased risk of developing non-serous ovarian cancer. Our work demonstrates that sex steroid metabolism is important in the etiology of non-serous ovarian cancers and supports a heterogeneous hormonal etiology across histologic subtypes of ovarian cancer.",
keywords = "androgen metabolites, androgenic activity, endogenous androgens, heterogeneity, nested case–control study, ovarian cancer risk",
author = "Britton Trabert and Michels, {Kara A.} and Anderson, {Garnet L.} and Brinton, {Louise A.} and Falk, {Roni T.} and Geczik, {Ashley M.} and Harris, {Holly R.} and Kathy Pan and Pfeiffer, {Ruth M.} and Lihong Qi and Thomas Rohan and Nicolas Wentzensen and Xia Xu",
note = "Funding Information: The authors would like to also acknowledge the following short list of WHI investigators: Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller. Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg. Investigators and Academic Centers: (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker. This work was supported in part by The Intramural Research Program of the National Cancer Institute (B.T, L.A.B., R.T.F., A.M.G., K.A.M., R.M.P., N.W.). National Cancer Institute funding (K22 CA193860 to H.R.H.). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C (G.L. Anderson). For a list of all the investigators who have contributed to WHI science, please visit: https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf. Funding Information: Key words: endogenous androgens, androgen metabolites, androgenic activity, ovarian cancer risk, nested case–control study, heterogeneity Abbreviations: 3α-diol-17G: 5α-androstane-3α,17β diol-17-glucuronide; 3α-diol-3G: 5α-androstane-3α,17β diol-3-glucuronide; 5α-androstanedione: 5α-androstane-3,17-dione; ADT: androsterone; ADT-G: androsterone-glucuronide; BMI: body mass index; CI: confidence interval; CV: coefficient of variation; DHEA: dehydroepiandrosterone; DHEAS: and its metabolite dehydroepiandrosterone sulfate; DHT: dihydrotestosterone; DHTS: dihydrotestosterone sulfate; ICC: intraclass correlation coefficient; LC–MS/MS: liquid chromatography–tandem mass spectrometry; OR: odds ratio; OS: Observational Study; WHI: Women{\textquoteright}s Health Initiative Additional Supporting Information may be found in the online version of this article. Conflicts of interest: All authors declare they have no conflicts of interest. Grant sponsor: National Heart, Lung, and Blood Institute; Grant numbers: HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN268201100046C, HHSN271201100004C ; Grant sponsor: National Cancer Institute; Grant number: K22 CA193860; Grant sponsor: The Intramural Research Program of the National Cancer Institute DOI: 10.1002/ijc.32157 History: Received 1 Oct 2018; ; Accepted 10 Jan 2019; Online 26 Jan 2019 Correspondence to: Britton Trabert, 9609 Medical Center Drive, Bethesda, MD 20892-9768, Tel.: 240-276-7331, Fax: 240-276-7838, E-mail: britton.trabert@nih.gov Funding Information: 1Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 2Division of Public Health Sciences, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 3Division of Public Health Sciences, Epidemiology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 4Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 5Public Health Sciences, School of Medicine, UC Davis, Sacramento, CA 6Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 7Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 8Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA Funding Information: We excluded women with unconjugated estrone concentrations greater than or equal to 184 pmol/l (~50 pg/mL; n = 10), which is typically indicative of exogenous hormone use, as well as 2 control women who did not have sufficient serum to measure circulating androgens after estrogen metabolites were measured in a prior analysis.17 The present study included 169 ovarian cancer cases and 410 matched controls. Among ovarian cancer cases, 102 had serous tumors and the remaining 67 had non-serous cancers (13 endometrioid, 11 clear cell, 9 mucinous, and 34 other-epithelial subtypes). Approval for conducting WHI was obtained from human subjects review at the Fred Hutchinson Cancer Research Center (WHI Clinical Coordinating Center) and all 40 clinical centers. The current project was reviewed and exempted by the Office of Human Subjects Research at the U.S. National Cancer Institute. Written informed consent was obtained from study participants.",
year = "2019",
month = oct,
day = "15",
doi = "10.1002/ijc.32157",
language = "English (US)",
volume = "145",
pages = "2051--2060",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "8",
}