Letter to the Editor: Superior Mass Spectrometry-Based Estrogen Assays Should Replace Immunoassays

Please find what we strongly believe is particularly important for accurate estrogen assays: A conclusion in the statement recently published following the Pooks Hill Workshop (1) that is particularly difficult to understand is: “Both immunoassays and mass spectrometry (MS)-based assays for estrogens and their metabolites would be acceptable if they are accurate and reliable and meet performance criteria suitable for their intended use.” The problem is that nobody can tell when immuno-based assays are “accurate and reliable.” This is due to issues of specificity, selectivity, precision, and reproducibility of the immunoassays (2, 3). In fact, it has been clear for quite some time that the immunoassays should be replaced by validated MS-based assays (4). Immunoassays are a technology of the 1970s that has been very useful. However, two main biases can never be quantitated: 1) lack of specificity is impossible to control in immunoassays; and 2) matrix effects are also not controllable in immunoassays. Moreover, the standard should not be an agreed upon or some “gold” standard (imprecise, often incorrect) but an absolute/true standard. The same difficulty applies to the continuation of the same phrase which reads: “… and meets performance criteria suitable for their intended use.” It is very important to make available the range of normal values for estrogens, but this information has been available for quite some time using MS-based assays. The harmonization that consists in having different laboratories obtaining the same value is not a guarantee of accuracy because all the laboratories involved could well have wrong values. It is true that not every MS-based assay provides valid accurate data if not properly validated and/or not well controlled during assays (5). The standard used in MS-based assays must be an absolute/true reference with certificate of analysis including HPLC profile, HPLC assay, Nuclear Magnetic Resonance, Infrared spectroscopy and residual solvents. Laboratories should have the means and obligation to determine the purity/trueness of the standards used. It is also true that MS-based assays are more expensive and more technically demanding, but this is what is required to obtain accurate data. In fact, all research is costly, and the total expenses of any study are a complete loss if the data are not valid and accurate. “A long-term goal of requiring accurate assays” is not an appropriate statement because accurate assays should be an immediate and not a long-term goal. Please consider how many clinical trials including large epidemiological studies have been performed at high costs but were using unreliable steroid data (6). These clinical trials would need to be repeated due to the problems of the immuno-based assays used to “save costs”?? The accuracy item of the summary (1) would benefit from being focused on the true 2015 situation, not on costs, availability, technical difficulties, etc. Most importantly, if the estrogen assays are done using a validated MS-based technology, there will be no significant differences in the data obtained in different laboratories. Disclosure Summary: F.L. (CEO of EndoCeutics), Y.K., and R.G. are employees of EndoCeutics, developer of MS-based steroid assays. A.B. is a consultant of EndoCeutics. mass spectrometry.

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