Measuring estrogen exposure and metabolism: workshop recommendations on clinical issues

Abstract

The Pooks Hill workshop on “Measuring Estrogen Exposure and Metabolism” addressed key clinical and research issues reflected by the title. This meeting brought together 25 experts as speakers and an additional 75 attendees. Principal sponsors for the meeting were The Endocrine Society, the American Association for Clinical Chemistry (AACC), and the Partnership for Accurate Testing of Hormones (PATH), with meeting coordination by Penn State Continuing Education. After the 25 formal presentations and discussion, time was devoted to obtaining opinions on clinical issues related to the measurement of the estrogens and their metabolites. The discussion regarding research issues and the opinions expressed will be formulated and published separately. The clinical recommendations of the workshop participants are highlighted below, and the following paragraphs summarize the conclusions in more detail, as compiled by the workshop steering committee, the authors of this manuscript. A special issue of the journal Steroids contains the manuscripts summarizing most of the individual presentations. Stakeholders should acknowledge the importance of standardization and harmonization and thus support the efforts of the Centers for Disease Control and Prevention (CDC) or alternative strategies to arrive at measurement methods for estrogens and their metabolites (see Glossary for definitions) that are accuracy-based and reliable. Both immunoassays and mass spectrometry-based assays for estrogens and their metabolites (see Glossary for definitions) would be acceptable if they are accurate and reliable and meet performance criteria suitable for their intended use. A study to evaluate the different approaches for validation of estrogen assay accuracy should be conducted to assess the general applicability and to obtain further information about the strengths and limitations of each approach. Reference ranges for estradiol need to be established in postmenopausal women and in prepubertal and pubertal boys and girls (age and Tanner stage-specific within each gender) using validated, standardized assays. The Standards of Reporting Diagnostic Accuracy (STARD) criteria should be updated to require data on a clinical assay's accuracy (trueness) or bias compared to an accepted reference method. It was recommended that journals, at this time, require a statement regarding accuracy assessment for estrogen and estrogen metabolite assays with a long-term goal of requiring measurements using accurate assays. Sex steroid hormone measurements are widely employed in patient care using either immunoassay or mass spectrometry-based methods. Problems associated with the accuracy and precision of these measurements, particularly with immunoassays in select populations, have been reported for several years (1, 2). The recognition of the negative impact this has had on research and clinical management led to recommendations not to use certain assays for clinical care and scientific publication (3, 4). Efforts are under way to address these limitations and the need for improved hormone tests to enable better patient care. Emanating from a meeting of experts sharing a broad perspective and interest in T standardization, great progress has been made toward standardizing T assays (4). Similarly, there is currently a lack of adequate performance and standardization among assays for estrogens and their metabolites (3). This impacts clinical decision-making and patient care, particularly at low estrogen concentrations, because measurements by different methods may not yield the same numeric result. Reference ranges for estrogens also vary based on the specific assay used and may not be available for relevant populations, which, due to assay inadequacies, further complicates appropriate clinical care. Once methods are standardized or harmonized, reference ranges will need to be established in postmenopausal women as well as prepubertal and pubertal boys and girls. These ranges should be age- and puberty stage-specific, within each gender. Clinical laboratories performing estrogen measurements have often established such ranges, but these differ across labs and do not translate across methods. Meeting attendees generally agreed that stakeholders should acknowledge the importance of standardization and harmonization for clinical laboratory measurement procedures and support the efforts of the CDC or other alternative strategies described below to arrive at estrogen methods that are accuracy-based and reliable. Standardization is possible for analytes for which primary (pure substance) reference materials and/or reference measurement procedures are available. A roadmap for harmonization of laboratory measurement procedures was published in 2011 and describes approaches to harmonize results for analytes that do not have primary reference materials or reference method procedures (5). The CDC Hormone Standardization (HoSt) Program consists of three steps: developi