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Submitted on May 2, 2005
Accepted on August 12, 2005
RCPA/AACB Chemical Pathology Quality Assurance Programs Pty Ltd, Flinders Medical Centre, Bedford Park, South Australia, Australia; Prince Henry's Institute of Medical Research, Monash Medical Centre, Clayton, Victoria, Australia; Australian Sports Drug Testing Laboratory, National Measurement Institute, Pymble, NSW, Australia; Andrology Australia, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia; Department of Andrology, Concord Hospital, ANZAC Research Institute, University of Sydney, Sydney, NSW, Australia
* To whom correspondence should be addressed. E-mail: djh{at}anzac.edu.au.
Context. Management of male infertility and/or androgen deficiency requires accurate hormonal measurements with valid reference intervals.
Objective. To develop a valid reference panel of blood samples from healthy eugonadal young men with verified normal reproductive function. To use this panel to evaluate the performance of 7 fully automated commercial multiplex immunoassay platforms used to measure serum total testosterone (T), LH and FSH.
Design. Observational study of consistency between 7 different automated immunoassays for each of total T, LH and FSH. Each method was implemented in two laboratories each repeating the analysis of the full reference panel samples twice. Serum T concentration was also measured by gas chromatography/mass spectrometry (GC/MS) and serum inhibin B levels by an enzyme-linked immunosorbent assay.
Setting. Commercial, high volume clinical pathology laboratories
Participants. From 147 men screened, sera from 124 healthy reproductively normal men (age 21-35 yr) with normal sperm output was used as a reference panel. All laboratories selected for elite performance in the national immunoassay quality assurance program agreed to participate.
Main Outcome Measure(s). For each of 868 assays, descriptive statistics were calculated in the natural and log-transformed scales and analyzed by nested, repeated measures ANOVA after log-transformation. Reference intervals, defined as 95% confidence limits, were calculated using arithmetic (natural scale), geometric (log-scale) and non-parametric methods.
Results. Descriptive statistics and reference intervals for serum T, LH and FSH differed widely and significantly between methods but variation between laboratories for the same assay was negligible. All T method showed significant differences in regression slope and intercept in deviance plots as well as in estimated reference ranges compared with the independent GC/MS reference method. Although similar between-method differences existed for gonadotropin assays, the smaller quantitative discrepancies allowed assignment of consensus reference intervals for serum FSH (1.3-8.4 IU/L) and LH (1.6-8.0 IU/L) though these differed from manufacturers currently quoted expected values.
Conclusions. Using a reference panel of sera from healthy, eugonadal young men with verified normal reproductive function, major differences exist between commercial T immunoassays as well as divergence from the GC/MS standard. This impairs their clinical diagnostic utility and requires substantial improvements in automated T immunoassay technologies or a switch to GC/MS methods. Gonadotropin assays showed less variability but current high throughput immunoassays remain suboptimal to confirm accurate diagnosis of azoospermia or androgen deficiency.
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