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Workshop on Normal Reference Ranges for Estradiol in Postmenopausal Women, September 2019, Chicago, Illinois

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Workshop on Normal Reference Ranges for Estradiol in Postmenopausal Women, September 2019, Chicago, Illinois Menopause: The Journal of The North American Menopause Society Vol. 27, No. 6, pp. 614-624 DOI: 10.1097/GME.0000000000001556 ß 2020 by The North American Menopause Society SYMPOSIUM REPORT Workshop on normal reference ranges for estradiol in postmenopausal women, September 2019, Chicago, Illinois Richard J. Santen, MD,1 JoAnn V. Pinkerton, MD, FACOG, NCMP,2 JamesH.Liu,MD,NCMP,3 Alvin M. Matsumoto, MD, FACP,4 Roger A. Lobo, MD, FACOG,5 Susan R. Davis, MBBS, FRACP, PhD, FAHMS,6 and James A. Simon, MD, CCD, NCMP, IF, FACOG7 Abstract The North American Menopause Society (NAMS) organized the Workshop on Normal Ranges for Estradiol in Postmenopausal Women from September 23 to 24, 2019, in Chicago, Illinois. The aim of the workshop was to review existing analytical methodologies for measuring estradiol in postmenopausal women and to assess existing data and study cohorts of postmenopausal women for their suitability to establish normal postmenopausal ranges. The anticipated outcome of the workshop was to develop recommendations for establishing normal ranges generated with a standardized and certified assay that could be adopted by clinical and research communities. The attendees determined that the term reference range was a better descriptor than normal range for estradiol measurements in postmenopausal women. Twenty-eight speakers presented during the workshop. Key Words: Estradiol – Estradiol assays – Estradiol workshop – Estrogen – Menopause. rs. Matsumoto, Pinkerton, Liu, and Santen opened purification steps (ie, those on automated platforms) lack the workshop by discussing the rationale and goals sensitivity, specificity, accuracy, and standardization. In for the workshop. They noted that this workshop addition, differences exist in the characteristics of patient pop- D 1,2 resulted because estradiol levels reported for postmenopausal ulations used to determine reference ranges. Current state-of- women were highly variable, with concentrations depending the-art assays involve tandem mass spectrometry in combination on the assay used. Accordingly, no universally accepted with separation either by gas chromatography (GC) or liquid reference range for estradiol was available for clinicians chromatography (LC). Contemporary approaches to developing and researchers. A major reason for this variability is that reference ranges involve harmonization of various assays immunoassays for estradiol without one or more preceding between laboratories using well-characterized and validated Received February 6, 2020; revised and accepted February 6, 2020. Pharmaceuticals, Pfizer Australia; Grant/Research Support: National From the 1University of Virginia Health System, Division of Endocri- Health and Medical Research Council of Australia, The Grollo Ruzzene nology and Metabolism, Charlottesville, VA; 2University of Virginia Foundation. J.H.L., reports: Consultant/Advisory Board: Allergan, Health System, Division of Midlife Health, Charlottesville, VA; Amag, Bayer, Dare Bioscience, Ferring, Mitsubishi, TherapeuticsMD; 3Department of Obstetrics and Gynecology, University Hospitals Cleve- Research Grants: AbbVie, Allergan, Amag, Dare Bioscience, Femasys. land Medical Center, Case Western Reserve University, Cleveland, OH; All funds paid to the institution. R.A.L., reports: Consultant/Advisory 4Geriatric Research Education and Clinical Center, VA Puget Sound Board: Amag, Mithra, TherapeuticsMD, Sojournix, Exeltis; Grant/ Health Care System and Department of Medicine, Division of Geron- Research Support: TherapeuticsMD, Bayer, NIH. A.M.M., reports: Con- tology and Geriatric Medicine, University of Washington School of sultant/Advisory Board: US Anti-Doping Agency, Partnership for Clean Medicine, Seattle, WA; 5Department of Obstetrics and Gynecology, Competition; Grant/Research Support: AbbVie, GlaxoSmithKline. College of Physicians and Surgeons, New York, NY; 6Monash Univer- J.V.P., reports no relevant financial relationships. R.J.S., reports: Con- sity, School of Public Health and Preventive Medicine, Melbourne, sultant/Advisory Board: TherapeuticsMD. J.A.S., reports: Consultant/ Australia; and 7George Washington University, Women’s Health and Advisory Board: AbbVie, Allergan, Amag, Amgen, Ascend, Bayer, Ceek Research Consultants, Washington, DC. Enterprises, Covance, Dare Bioscience, Duchesnay, Hologic, NeRRe/ Support/Funding organizations: The North American Menopause Soci- KaNDy, Mitsubishi Tanabe, ObsEva SA, Palatin, Sanofi, Shionogi, ety, The American Society for Reproductive Medicine, The Centers for Sprout, TherapeuticsMD; Speakers’ Bureau: AbbVie, Amag, Duchesnay, Disease Control and Prevention, The Endocrine Society and the Partner- Novo Nordisk, Shionogi, TherapeuticsMD; Grant/Research Support: ship for the Accurate Testing of Hormones, The International Society for AbbVie, Allergan, Agile, Bayer, Endoceutics, GTx, Ipsen, Myovant the Study of Women’s Sexual Health, The University of Virginia, Sciences, New England Research Institute, ObsEva, Palatin, Symbio Division of Endocrinology and Metabolism, The International Meno- Research, TherapeuticsMD. pause Society. Supplemental digital content is available for this article. Direct URL Funding companies: Abbott Laboratories, Ansh Labs, ARUP Labs, citations are provided in the HTML and PDF versions of this article on the Endoceutics, Novo Nordisk, Quest Diagnostics, TherapeuticsMD. journal’s Website (www.menopause.org). Financial disclosure/conflicts of interest: S.R.D., reports: Consultant/ Address correspondence to: The North American Menopause Advisory Board: Que Oncology, Mayne Pharmaceuticals, Roche Society, 30100 Chagrin Blvd., Suite 210; Pepper Pike, OH 44124. Pharmaceuticals; Speaker Honoraria: Besins Healthcare, Lawley E-mail: [email protected]. 614 Menopause, Vol. 27, No. 6, 2020 REFERENCE RANGES FOR ESTRADIOL reference standards, similar to that used to develop a harmonized requested. Supporting companies did not participate in the reference range for serum total testosterone.3 Before the work- writing, review, revisions, conclusions, or approval of this shop, several factors in developing reference ranges were iden- report. tified for discussion, including the type of population to be used; identification of sensitive, accurate, and standardized estradiol ASSAY MEASUREMENT ISSUES assays; and use of direct versus indirect methods for reference A thorough data review provided compelling evidence that range development.4 mass spectrometry-based assays, after full validation and The North American Menopause Society (NAMS) has standardization, should be used in determining reference spent considerable effort identifying the possible risks of ranges for postmenopausal women and patients with clinical low-dose vaginal estrogen administration. NAMS’ guidelines conditions characterized by low estradiol levels. The group for the treatment of menopause recommend the use of vagi- agreed that certain highly characterized radioimmunoassays nally delivered estrogens to treat the genitourinary syndrome using extraction and column chromatography might be used of menopause (GSM) for certain patients. Possible risks listed but only after Centers for Disease Control and Prevention in boxed warning for low-dose vaginal estradiol include (CDC) certification for accuracy and standardization. A breast cancer, coronary artery disease, stroke, deep venous detailed review of existing data indicated that immunoassays thrombosis (DVT), pulmonary embolism, and probably detect higher levels of estradiol than do mass spectrometry dementia. However, it is reasonable to conclude that if assays, but the precise reasons for the overestimation are estrogen levels from low-dose vaginal estrogen do not exceed presently unknown.5 The data presented suggested that it the reference range established for postmenopausal women, might be useful to measure estradiol and estrone levels in such risks would be rare, unlikely, and difficult to identify. the same samples in situations in which prior data demon- During extensive literature review, it was recognized strated that each estrogen provided independent clinical that no reference ranges for postmenopause estradiol information. At the present time, cost limits the routine levels have been established and universally agreed on. measurement of both estradiol and estrone by mass spectrom- Determination of accurate systemic levels of estradiol etry; but assay capability is not at issue. Age, BMI, and body and estrone allows determination and standardization of weight all influence plasma estradiol and estrone levels, as the references range of postmenopausal estrogen levels demonstrated in several studies, but alcohol, tobacco use, and to further research into the effects of exogenous and endog- age of menopause exert lesser or nonsignificant effects.6 enous estrogens on important health concerns for postmen- opausal women. DEVELOPING REFERENCE RANGES A key goal of the workshop was to provide a roadmap for WORKSHOP GOALS developing reference ranges for estradiol in postmenopausal 1. Develop a roadmap for the methodology necessary to women. Jones discussed two methods, one called direct, develop accurate and precise standardized reference range for plasma estradiol in postmenopausal women. which uses well-characterized controls, and indirect, which 2. Compile existing data regarding postmenopause estradiol employs large data sets and mathematically excludes out- 6 levels using highly sensitive, specific, and precise mass liers. The speakers concluded that the direct method
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