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Standardization of Steroid Hormone Assays: Why, How, and When?

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Standardization of Steroid Hormone Assays: Why, How, and When? 1713 Commentary Standardization of Steroid Hormone Assays: Why, How, and When? Frank Z. Stanczyk,1 Jennifer S. Lee,2 and Richard J. Santen3 1Departments of Obstetrics and Gynecology, and Preventive Medicine, University of Southern California, KeckSchool of Medicine, Women’s and Children’s Hospital, Los Angeles, California; 2Division of Endocrinology, Clinical Nutrition, and Vascular Medicine, Department of Internal Medicine, University of California at Davis, Sacramento, California; and 3Clinical Research, Cancer Center, University of Virginia, Charlottesville, Virginia Abstract Lack of standardization of high-quality steroid hor- lation with biological variables such as body mass mone assays is a major deficiency in epidemiologic index. Similar problems exist with measurements of studies. In postmenopausal women, reported levels of E2 and estrone in men, and estrone and testosterone B serum17 -estradiol (E2) are highly variable and median in women. Interest in mass spectrometry–based assays normal values differ by approximately a 6-fold factor. is increasing as potential gold standard methods with A particular problemis the use of E 2 assays for pre- enhanced sensitivity and specificity; however, these diction of breast cancer risk and osteoporotic fractures, assays require costly instrumentation and highly where assay sensitivity may be the most important trained personnel. Taking all of these issues into con- factor. Identification of women in the lowest categories sideration, we propose establishment of standard pools of E2 levels will likely provide prognostic information of premenopausal, postmenopausal, and male serum, that would not be available in a large group of women and utilization of these for cross-comparison of various in whomE 2 levels are undetectable by less sensitive methods on an international basis. An oversight group assays. Detailed and costly methods involving extrac- could then establish standards based on these com- tion and chromatography in conjunction with RIA pro- parisons and set agreed upon confidence limits of vide generally acceptable E2 results in postmenopausal various hormones in the pools. These criteria would serum, whereas less tedious, direct immunoassays suf- allow validation of sensitivity, specificity, precision, fer frominadequate specificity and sensitivity. Studies and accuracy of current steroid hormone assay method- comparing the two types of methods generally report ology and provide surrogates until a true gold standard higher E2 values with the direct methods as a result of can be developed.(Cancer Epidemiol Biomarkers Prev cross-reactivity with other steroids and reduced corre- 2007;16(9):1713–9) Introduction High-quality steroid hormone assays with very good atically to inconsistent results and varied interpretations sensitivity, specificity, and reproducibility are essential across epidemiologic studies. to the validity of epidemiologic studies. Steroid hormone The lackof standardization of high-quality steroid measurements play a critical role in a variety of studies. hormone assays is a major deficiency in epidemiologic Among these are epidemiologic investigations of many studies, resulting in varying findings in hormone major diseases, including osteoporotic fracture, cognitive concentrations and hindering the ability to draw defin- dysfunction, and hormonally related cancers, including itive quantitative conclusions. This problem is particu- cancers of the breast, ovary, endometrium, prostate, and larly relevant regarding low levels of steroid hormones h testes. However, epidemiologic studies use many differ- such as 17 -estradiol (E2) and estrone (E1) in postmen- ent assay methods with varying performance. This is opausal women and men, and testosterone in women. evident, for example, in a survey of recent large The majority of E2 assays suffer from lackof sufficient epidemiologic studies of bone health in postmenopausal sensitivity, specificity, precision, and/or accuracy. No women (Table 1; refs. 1-6). Use of different assay gold standard exists to allow objective validation and methods with varying performance contributes problem- cross comparisons among various assays to ensure maximal quality control. An example in which this problem is particularly significant is in assessing breast cancer riskassociated with low E 2 levels (<30 pg/mL) Received 9/10/06; revised 6/19/07; accepted 7/2/07. in postmenopausal women. To clarify the relation Requests for reprints: FrankZ. Stanczyk,Departments of Obstetrics and Gynecology, and Preventive Medicine, University of Southern California, KeckSchool of between endogenous E2 levels and breast cancer riskin Medicine, Women’s and Children’s Hospital, Room 1M2, 1240 North Mission the setting of varied assay methods, limited statistical Road, Los Angeles, CA 90033. Phone: 323-226-3220; Fax: 323-226-2850; E-mail: [email protected] power, modest effect estimates, and limited variation Copyright D 2007 American Association for Cancer Research. in hormone levels across individual studies, a pooled doi:10.1158/1055-9965.EPI-06-0765 analysis of nine epidemiologic studies of endogenous Cancer Epidemiol Biomarkers Prev 2007;16(9). September 2007 Downloaded from cebp.aacrjournals.org on September 26, 2021. © 2007 American Association for Cancer Research. 1714 Standardization of Steroid Hormone Assay b postmenopausal hormones and breast cancer riskwas testosterone in women and E2 in men); ( ) provide a conducted (7). This study highlighted both the approx- perspective as to potential approaches to assay standard- imate 6-fold difference in median values among studies ization; and (c) project when standardization of such (range of median values in normal postmenopausal assays may be accomplished. women, 6.0-37 pg/mL), and the wide range of detection limits (from 0.8 to 10 pg/mL) for the E2 assay methods Immunoassay Methods used. Similar issues exist for measurement of serum levels of E2 and E1 in studies of men with benign Extraction/Chromatographic RIAs. Most of our prostatic hyperplasia and prostate cancer. knowledge about the physiologic and diagnostic role of These discrepancies in assay performance particularly steroid hormones in women and men is derived from limit investigations where comparisons of absolute, studies in which circulating levels of these compounds rather than relative, values of sex hormone concentra- were measured by radioimmunoassay (RIA) methods. tions are needed. Currently, estimating disease riskin The basis for the first RIA method was described in 1959 relation to serum sex steroids relies on comparing by Yalow and Berson, who showed that [131I]insulin could relative risks of disease across tertiles or quartiles of be displaced by nonradioactive insulin from insulin- sex steroid concentrations. This epidemiologic approach binding protein, and that [131I]insulin was inversely and relies less on an assay producing accurate measurements quantitatively related to the total amount of insulin of absolute concentration values. A sex steroid measure- present (8). Subsequently, specific antisera to human ment will likely be classified into the correct tertile insulin were prepared and resulted in the first RIA, with or quartile category as long as it is not near the border sufficient sensitivity to detect endogenous insulin in of two categories, thereby helping to circumvent assay human blood (9). A new era in reproductive endocrinol- inaccuracies. However, direct comparisons of sex hor- ogy was launched when Odell et al., in 1967, developed mone data across epidemiologic studies and recommen- the first RIAs for luteinizing hormone and follicle- dations about the use of hormone assays in the clinical stimulating hormone (10), and Abraham developed the setting would be facilitated by the use of assays across first E2 RIA in 1969 (11). The RIA methodology developed studies that provide both accurate and precise measure- by Yalow and Berson became highly successful because it ments. Determining accurate absolute concentration offered a general system for measurement of an values becomes essential, for example, to examine dose- immensely wide range of compounds of clinical and response relationships with exogenous hormone use or biological importance. effects of clinically relevant hormonal threshold levels for The first steroid RIA method, which was developed by disease outcomes. Current assay limitations potentially Abraham to quantify circulating levels of E2 (11, 12), hinder further understanding of the biological signifi- consisted of purification of E2 in serum or plasma cance of serum sex steroids and the ability to make samples by organic solvent extraction and column clinical recommendations about hormonal strategies for chromatography, before its quantification by RIA. A prevention and treatment, based on actual concentration small amount of tritiated E2 was added to the samples values. Furthermore, misleading information may be first to correct for procedural losses. Organic solvent obtained if no attempt is made to determine how well extraction removed the unconjugated steroids, leaving assay measurements correlate against those obtained behind all water-soluble conjugated steroids (sulfates by a gold standard assay. This is especially true when and glucuronides). Conjugated steroids are present in commercial kits are used for measuring steroid hormones considerably higher concentrations than unconjugated in epidemiologic studies. Assays done with such kits are steroids in blood. Thus, conjugated steroids
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