Challenges to the measurement of estradiol: an endocrine society position statement

Abstract

Objective: The objective of the study was to evaluate the current state of clinical assays for estradiol in the context of their applications.

Participants: The participants were appointed by the Council of The Endocrine Society and charged with attaining the objective using published data and expert opinion.

Evidence: Data were gathered from published sources via online databases (principally PubMed, Ovid MEDLINE, Google Scholar), and the clinical and laboratory experience of the participants.

Consensus process: The statement was an effort of the committee and was reviewed by each member. The Clinical Affairs Committee, the Council of The Endocrine Society, and JCEM reviewers reviewed the manuscript and made recommendations.

Conclusions: The measurement of estradiol in biological fluids is important in human biology from cradle to grave. In addition to its centrality in sexual development, it has significant effects on skin, blood vessels, bone, muscle, coagulation, hepatic cells, adipose tissue, the kidney, the gastrointestinal tract, brain, lung, and pancreas. Alterations in its plasma concentration have been implicated in coronary artery disease, stroke, and breast cancer. Although modern immunoassays and liquid chromatography/tandem mass spectrometry-based methods for estradiol are reasonably well suited to the diagnosis and management of infertility (nonetheless, imprecision and method-to-method differences remain problematic), the very low concentrations that appear to be crucial in nonreproductive tissues are a separate and more difficult issue. Such levels of estradiol are too low to be routinely measured accurately or precisely, and further evolution of analytical methods and the way in which estradiol is standardized is needed.

Figure 1.

Historical and current technical challenges to E2 assays with regard to analytical sensitivity. The primary methods used for clinical measurements are shown along the bar over a scale of E2 levels encompassing the situations in which measuring E2 in peripheral circulation is useful. (Detailed procedures for determining the limit of quantitation (LOQ) are available from the Clinical and Laboratory Standards Institute [CLSI EP17, http://www.abrf.org/index.cfm?method=list.getAttachment&disclaimerAck=1&msg=83913&att=688]). In this figure, a “rule-of-thumb” definition for the limit of quantitation (or minimal detectable dose [MDD]) is used; ie, the lowest concentration that can be measured with a coefficient of variation (CV) of 20% (19). It is useful to keep in mind that the 95% CI for a measure at this level is the mean ± 2 SD of repeated measurements. In other words, if the limit of quantitation is 80 pg/mL, values between 48 and 112 pg/mL cannot be distinguished with 95% confidence. The LOQ is typically dependent, among other things, on the operational condition of the instrument and the quality of reagents used; it therefore often differs in routine clinical laboratories when compared to the conditions under which the assay is first characterized and evaluated.