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POSITION STATEMENT |
St. Luke’s/Roosevelt Hospital Center and Columbia University College of Physicians and Surgeons (W.R.), New York, New York 10019; Division of Endocrinology and Metabolism (R.J.A.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Center for Androgen Related Disorders and Department of Obstetrics-Gynecology (R.A.), Cedars-Sinai Medical Center and Department of Obstetrics-Gynecology and Department of Medicine, The David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90048; Reproductive Endocrine Unit (Department of Medicine) and Department of Pathology (P.M.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; and Endocrine Research Laboratory (H.R.), Aurora St. Luke’s Medical Center, Division of Endocrinology, Metabolism, and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin 53215
To whom correspondence and reprint requests should be addressed: William Rosner, M.D., Department of Medicine, St. Luke’s/Roosevelt Hospital Center, 1000 Tenth Avenue, AJA 403, New York, New York 10019. E-mail: wr7{at}columbia.edu.
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Abstract |
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 Top Abstract 1. Introduction2. Background3. Methods for Measuring...4. Methods for Measuring...5. Uses of T...6. Normal Ranges for...7. Summary of Key...References |
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Participants: The five 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 gleaned from published sources via online databases (principally PubMed, Ovid MEDLINE, Google Scholar), the College of American Pathologists, and the clinical and laboratory experiences of the participants.
Consensus Process: The statement was an effort of the committee and was reviewed in detail by each member. The Council of The Endocrine Society reviewed a late draft and made specific recommendations.
Conclusions: Laboratory proficiency testing should be based on the ability to measure accurately and precisely samples containing known concentrations of testosterone, not only on agreement with others using the same method. When such standardization is in place, normative values for total and free testosterone should be established for both genders and children, taking into account the many variables that influence serum testosterone concentration.
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1. Introduction |
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TopAbstract1. Introduction2. Background3. Methods for Measuring...4. Methods for Measuring...5. Uses of T...6. Normal Ranges for...7. Summary of Key...References |
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The Council of The Endocrine Society, after noting that substantial difficulties exist in the measurement of T in biological fluids, appointed a task force, consisting of the authors of this position paper, to review the problem and make recommendations based on that review. The task force reviewed the literature, gathered data by interview and discussion to assess current practice, evaluated proficiency survey data from the College of American Pathologists (CAP), and came to consensus by both discussion and revision of drafts of the manuscript. The manuscript was reviewed by the Council; their comments were evaluated and included, if appropriate, before finalizing the document.
The problems of sensitivity and specificity of T assays have been addressed by extracting steroids from plasma or serum and separating them chromatographically before subjecting them to immunoassay. These methods are labor intensive and expensive. Hence, high-throughput, relatively inexpensive methods are in wide use that employ whole serum or plasma ("direct" assays) but, for the most part, are too insensitive and inaccurate to measure the total T (TT) concentration in the plasma of women and children. We have the technology to improve the accuracy and precision of T assays and must choose these properties over simplicity and economy.
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2. Background |
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TopAbstract1. Introduction2. Background3. Methods for Measuring...4. Methods for Measuring...5. Uses of T...6. Normal Ranges for...7. Summary of Key...References |
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3. Methods for Measuring TT |
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TopAbstract1. Introduction2. Background3. Methods for Measuring...4. Methods for Measuring...5. Uses of T...6. Normal Ranges for...7. Summary of Key...References |
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. Following, we briefly detail these methods.
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RIAs and chemiluminescence immunoassays are the most widely used methods for measuring plasma TT. These assays are performed directly on serum or plasma or after extraction and/or chromatography. The more labor-intensive assays that incorporate extraction and chromatography offer several advantages, including removal of interfering proteins, separation of cross-reacting steroids, and use of large serum aliquots to increase sensitivity. Such assays are more accurate and sensitive than direct assays but still require proper validation.
b. Mass spectrometry (MS) methods for measuring TT
MS both identifies and quantifies the analyte and, for TT, routinely incorporates extraction and chromatography before assay (4, 5, 6, 7, 8, 9); the specificity of this method has been enhanced by tandem MS (MS-MS), which still must be validated for accuracy, sensitivity, and precision.
c. Comparison of TT assay methods
The CAP administers a quality-control program that distributes blinded samples to participating laboratories and gauges accuracy relative to others using the same methodology. The samples they distribute are not in plasma but in material that allows the samples to be stable, although not frozen, and hence more easily distributable to large numbers of laboratories. Assay results may very well be influenced by this artificial matrix. Table 2 shows the CAP results for three samples of TT expected for a normal woman [no. 1; 33 ± 11 ng/dl (1.1 ± 0.4 nM)], a hypogonadal man or an androgenized woman [no. 2; 97 ± 31 ng/dl (3.4 ± 1.1 nM)], and a normal man [no. 3; 465 ± 81 ng/dl (16.1 ± 2.8 nM)]. For no. 1, the coefficients of variation within the same methodology performed at different laboratories ranged from 13–32%. Results for the same sample using the same method varied 2- to 6-fold, demonstrating the unacceptable reliability of these methods for measuring TT in normal women. Examination of "All Instruments" for no. 1 indicates that clinical usefulness is severely compromised. As the concentration of T increases (no. 2 and 3), the coefficients of variation within a methodology decrease. However, there is still considerable variability and lack of standardization between methods as demonstrated by, for example, the range of values for no. 2 [45–365 ng/dl (1.6–12.7 nM)]. Approximately one third of all the laboratories used the same instrument and about two thirds used one of three instruments (Table 2). The widespread use of a limited number of methodologies gives promise that standardization is achievable. There are comparable problems with variability and a lack of standards for accuracy for FT.
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Taieb et al. (7) compared 10 direct commercial immunoassays with isotope-dilution gas chromatography-MS (ID/GC-MS) and also compared samples from 55 women by ID/GC-MS with an extraction and chromatography RIA (13) (Fig. 1). Below approximately 8.0 nM (230 ng/dl), the methods disagreed by up to 5-fold, with immunoassays generally overestimating the T concentration. Some of the methods were better than others, but even the best method showed up to a 2-fold higher T concentration by immunoassay in women. In men, seven of the 10 tested assays had highly statistically significantly different medians compared with ID/GC-MS. The salutary outcome is that three of the commercial assays had medians not significantly different from those measured by the MS-based method in men. Even this salve contains an irritant because "... this statistical analysis compared the differences between medians and did not address the scatter of the results between each immunoassay and ID/GC-MS." Thus, concern remains that even the good assays in men are only good on average.
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by comparing six different direct immunoassays to liquid chromatography/MS-MS (LC/MS-MS). Two of the assays tested were the same as shown in Fig. 1 and four were unique to this study. For T less than 150 ng/dl (<5.2 nmol/liter), the values were neither analytically nor clinically useful. For higher T concentrations, the values have some utility, but the discrepancies among methods are unacceptable. There are three additional studies that support these findings (14, 15, 16) and apparently none that contradict them. |
4. Methods for Measuring FT |
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TopAbstract1. Introduction2. Background3. Methods for Measuring...4. Methods for Measuring...5. Uses of T...6. Normal Ranges for...7. Summary of Key...References |
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An appropriate assay for TT is necessary but not sufficient for the measurement of FT. Because FT is such a tiny portion of TT, an assay that is accurate and precise when measuring very small amounts of T is required. The indirect measurement of FT is accomplished by adding 3H-T to the sample to be assayed and, after equilibrium has been attained, separating bound from free 3H-T, and then measuring free 3H-T. The fraction of free 3H-T is multiplied by the amount of TT, obtained in a separate assay from the same plasma. The major potential problem with such assays is the possible presence of radiochemical impurities. For example, a 2% contamination with a radioactive substance that does not bind to proteins will cause an apparent doubling of the FT in which 2% of T actually was free. If both direct and indirect methods are done well, they should yield the same answer.
b. Data on FT measurement
The values of FT by equilibrium dialysis (ED) are influenced by a number of variables, the most important of which is the assay for T. However, the details of how ED is done (21) as well as the population being studied all have an impact on the results. Before citing some examples of how FT is measured, our agreement with the following should be noted: "... it is clear that even the best available and scrupulously performed measurement procedures have technical and fundamental limitations and that, consequently, the scientific community will have to accept that there will remain a degree of arbitrariness about the best way to measure free hormone concentrations" (8). We believe that the degree of arbitrariness can be small and that the best approaches approximate the FT concentration.
c. Direct and indirect measurement of FT
Both Adachi et al. (22) and Van Uytfanghe et al. (8) measured FT by assaying for T in an ultrafiltrate of plasma or serum. The former study gave inadequate attention to the measurement of TT, thus invalidating the use of their results for this stringent review. The latter used a method based on GC-MS for the measurement of TT and paid close attention to the validation of their method. Even then, these investigators concluded that further sensitivity must be attained for the method to be useful in women.
To our knowledge, there is only one major study in which T was measured directly when FT was separated by ED (23). Although the work was meticulously performed, T was measured by a direct RIA using 125I-T as tracer, and the method was not validated against a criterion (gold) standard method. All of the other communications in which FT was measured by ultrafiltration or ED used the indirect method. Thus, when FT obtained by ED is compared with other methods, we are considering studies that use the indirect method. Otherwise, studies that measure FT do so by calculating it, using a surrogate for it [either the free androgen index (FAI) or bio-T], or a direct assay for FT. There is considerable confusion in the use of terms. For example, the term FT was used when what was reported was a surrogate (24, 25) or the calculated FAI was specified in the title and then reported as FT in nmol/liter (26).
d. Measurement of bioavailable T (bio-T)
Bio-T is albumin bound plus FT, the fraction thought to be available to tissues. It is measured by adding 3H-T to serum and precipitating SHBG bound 3H-T with ammonium sulfate. The fraction of 3H-T not precipitated is used to calculate bio-T by multiplying by the TT obtained in a separate assay. Variations in precipitation and assay methodology makes comparison of results between different communications difficult (27). Furthermore, the concept itself may be misleading and confusing. Despite this, bio-T has been reported to correlate with FT by ED from fairly (28) to extremely well (29) and to be a useful index of some biological changes (28).
e. The Free Androgen Index (FAI)
The FAI is the unitless quotient T/SHBG and depends on appropriate measurements for T and SHBG. Therefore, there is a reasonable correlation between FAI and FT, particularly in women. However, FT depends on not only the ratio but also the absolute concentration of both T and SHBG (30). Thus, the correlation will depend on these variables and will be biased, depending on the concentration of T as, at lower levels, measurements are less precise. This is illustrated by the range of correlations obtained by different investigators (29, 31, 32). Having measured both T and SHBG, FT should be calculated, which is easily done using a fixed formula in a spreadsheet or using a FT calculator (e.g. http://www.issam.ch/freetesto.htm).
f. One-step direct assay for FT
This assay, which uses an 125I-T analog, has been consistently found to be inaccurate (29, 32, 33), and its use is highly questionable.
g. Calculation of FT concentration
One can also use the law of mass action to calculate concentrations of T that are free or bound to SHBG and albumin (29, 34). The calculation depends on the measurement of TT, total SHBG and total albumin, and the use of the equilibrium dissociation constants (Kd) for the binding of SHBG and T and albumin and T. Within rather broad limits, the concentration of the low affinity binding protein, albumin, varies too little to significantly affect FT levels (29). Although the Kd for SHBG-T is about 1 nM, this number needs to be verified and universally agreed on. In addition, a universal standard for SHBG has not been agreed on. With those caveats, calculation of FT is the most useful estimate of FT in plasma (29, 32) except in pregnancy (29).
Calculation of FT compares extraordinarily well with FT measured by ED (29, 32, 35). Miller et al. compared calculation with ED in more than 400 women with a variety of disorders and looked at five clinical subgroups (32). The correlation coefficients between ED and calculation were greater than 0.96; the intercepts were not different from zero, but the slopes indicated a 20% bias between the measured and calculated values due either to a systematic error in the method used for ED or in the calculation. The error in the calculation, in turn, could arise from using the wrong Kd, errors in the measurement of SHBG, or both. Studies comparing calculation with ultrafiltration mostly (36), but not always (8), show excellent correlation.
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5. Uses of T Assays |
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TopAbstract1. Introduction2. Background3. Methods for Measuring...4. Methods for Measuring...5. Uses of T...6. Normal Ranges for...7. Summary of Key...References |
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a. Evaluating adult males
The most common use of clinical T assays is to diagnose hypogonadism in men for which almost any assay will do. Whether the subtle decrease in plasma T in the aging male is normal or represents hypogonadism will not be answered with the use of almost any assay. Furthermore, the evaluation of the risks and benefits of T replacement requires sensitive and accurate assays. When the TT lies near the lower limit of the normal range, a calculated FT may prove useful.
b. Evaluating adult females
The measurement of T in women is used for evaluating states of androgen excess to both exclude androgen-producing tumors and help in the diagnosis of other hyperandrogenic states. Most commercial assays are adequate for identifying, but not accurately quantifying, elevated TT in women. However, these assays frequently fail to detect the moderately androgenized patient, e.g. most patients with polycystic ovary syndrome (PCOS) (20). FT, or one of its surrogates, correlates better with the clinical presentation of these patients than does TT. FT measurements may be the most sensitive marker of hyperandrogenemia; they are above the upper normal limit in 60–70% of women with clinical signs and symptoms of hyperandrogenism (20).
The influence of T on female sexual desire and sense of well-being has received considerable attention; two studies have shown no correlation between circulating T concentrations and female sexual function (37, 38), although there is evidence that T replacement in ovariectomized premenopausal women (39) and those with hypopituitarism (40) confers some benefit. The normative values for T and FT across a woman’s life span are not adequate. Thus, the measurement of serum T for the evaluation of poor libido in women is unlikely to be informative, and we recommend that such measurements not be used for this purpose until improved methods are available.
c. Evaluating children
In boys, TT measurements are used during adolescence in the evaluation of early or delayed puberty or at birth during the evaluation of undervirilized males. In girls, TT assays are used to assess and treat disorders of sexual development and in the evaluation of contrasexual pubertal development. As in women, TT determination in children should be carried out only with assays of sufficient sensitivity and in conjunction with appropriate normative data. FT in children is of limited value.
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6. Normal Ranges for T |
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TopAbstract1. Introduction2. Background3. Methods for Measuring...4. Methods for Measuring...5. Uses of T...6. Normal Ranges for...7. Summary of Key...References |
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Although the measurement of TT in normal men does not represent a problem in sensitivity, a precise definition of the lower limit of normal TT for adult males remains elusive. Because the clinical presentation of hypogonadism is highly variable, particularly in the setting of comorbid conditions, hypogonadism is often a laboratory rather than clinical diagnosis. TT greater than 320 ng/dl (11.1 nM) is considered normal (41). TT less than 200 ng/dl (6.9 nM) is diagnostic of hypogonadism, but TT 200–320 ng/dl (6.9–11.1 nM) is equivocal. The agreement among platform assays is marginal in the difficult range of 200–320 ng/dl (6.9–11.1 nM) in which a difference of 10% might alter clinical decisions. Although standardization (or replacement) of platform assays with MS-based methods holds the promise of obviating the assay-based confusion at the lower end of the normal range, the variability in FT consequent to alterations in SHBG must be considered. Because T secretion is pulsatile and varies diurnally, more than a single measurement is sometimes required to make a therapeutic decision.
For values in the equivocal zone, the determination of FI or bio-T is recommended to distinguish eugonadism from hypogonadism. An FT of 6.5 ng/dl (0.23 nM) and a bio-T of 150 ng/dl (5.2 nM) are considered the lower limits of normal (41). Measurement of FT or bio-T does not avoid the problem of TT assay standardization, because both use TT as part of the measurement.
b. In adult women
The need for defining an accurate lower range for T in women has recently become significant. Platform and conventional RIAs are unreliable in this range, whereas immunoassay after extraction and chromatography or LC/MS-MS appears capable of yielding meaningful data.
In constructing normal ranges, care must be taken to exclude subjects with PCOS, or other forms of androgen excess. T distributions are bimodal in families of PCOS subjects (42) and normal ranges show a tail at the high end of the distribution. T in women varies not only with the menstrual cycle but also with age, race, and body mass index (38).
The FAI is often used as a surrogate for FT, and the FAI correlates well with FT in women (32) but not men. Because T production is regulated by gonadotropin feedback in men, changes in SHBG, which alter FT concentrations, will be compensated by autoregulation of T production but not so in women. In addition, much circulating T in women is derived from the peripheral conversion of adrenal dehydroepiandrosterone and dehydroepiandrosterone sulfate (43) that also is not subject to feedback control. Because SHBG is present in such large excess in women (10–100:1), FT concentrations are driven primarily by SHBG abundance. In addition, T excess in women lowers SHBG concentrations, which raises the FT concentration and contributes to the strong correlation of 1/SHBG with FT.
c. In children
The testes secrete large amounts of T during the first year of life, but gonadal steroidogenesis is very low in both boys and girls thereafter until the start of puberty. Consequently, T concentrations are extremely low throughout childhood; the measurement of T in children poses the same problems as those in women. Consequently, assay of T in children should use immunoassay after extraction and chromatography or LC/MS-MS (5). One recent report indicates that derivatization before LC/MS-MS improves assay characteristics (4). Total and FT reference intervals must specify gender, age, and Tanner stage, as has recently been done (5) because all these variables influence T concentrations. Normative data for infants are difficult to obtain, so historical data are used (44, 45).
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7. Summary of Key Findings and Recommendations |
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TopAbstract1. Introduction2. Background3. Methods for Measuring...4. Methods for Measuring...5. Uses of T...6. Normal Ranges for...7. Summary of Key...References |
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and 3. • Our most salient recommendation is: laboratory proficiency testing should be based on the ability to accurately and precisely measure a sample containing a known concentration of T and not only on agreement with peers using the same method. When such standardization is in place, normative values for TT and FT should be established taking into account all the appropriate variables, e.g. gender, age, race, stage of puberty, time of day, etc. We believe that this goal can be accomplished. It has been done for cholesterol. In the interim we offer the following recommendations to physicians ordering and using androgen assays:
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Footnotes |
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First Published Online November 7, 2006
Abbreviations: bio-T, Bioavailable T; CAP, College of American Pathologists; ED, equilibrium dialysis; FAI, free androgen index; FT, free T; ID/GC-MS, isotope-dilution gas chromatography-MS; Kd, dissociation constant; LC/MS-MS, liquid chromatography/MS-MS; MS, mass spectrometry; MS-MS, tandem MS; PCOS, polycystic ovary syndrome; T, testosterone; TT, total T.
Received August 24, 2006.
Accepted October 30, 2006.
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TopAbstract1. Introduction2. Background3. Methods for Measuring...4. Methods for Measuring...5. Uses of T...6. Normal Ranges for...7. Summary of Key...References |
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-hydroxy-progesterone, androstenedione and testosterone by tandem mass spectrometry with on-line extraction. Steroids 71:450–458[CrossRef][Medline] to human plasma proteins at body temperature. J Steroid Biochem Mol Biol 16:801–810This article has been cited by other articles:
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A. Mueller, L. J. Gooren, S. Naton-Schotz, S. Cupisti, M. W. Beckmann, and R. Dittrich Prevalence of Polycystic Ovary Syndrome and Hyperandrogenemia in Female-to-Male Transsexuals J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1408 - 1411. [Abstract] [Full Text] [PDF]
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K. A. Martin, R. J. Chang, D. A. Ehrmann, L. Ibanez, R. A. Lobo, R. L. Rosenfield, J. Shapiro, V. M. Montori, and B. A. Swiglo Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1105 - 1120. [Abstract] [Full Text] [PDF]
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R. S. Swerdloff and C. Wang Free Testosterone Measurement by the Analog Displacement Direct Assay: Old Concerns and New Evidence Clin. Chem., March 1, 2008; 54(3): 458 - 460. [Full Text] [PDF]
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K. S. Fritz, A. J.S. McKean, J. C. Nelson, and R. B. Wilcox Analog-Based Free Testosterone Test Results Linked to Total Testosterone Concentrations, Not Free Testosterone Concentrations Clin. Chem., March 1, 2008; 54(3): 512 - 516. [Abstract] [Full Text] [PDF]
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R. Azziz Diagnosing the diagnosis: why we must standardize the defining features of polycystic ovary syndrome Ann Clin Biochem, January 1, 2008; 45(1): 3 - 5. [Full Text] [PDF]
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D. J. Handelsman Update in Andrology J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4505 - 4511. [Abstract] [Full Text] [PDF]
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G. D. Braunstein The Endocrine Society Clinical Practice Guideline and The North American Menopause Society Position Statement on Androgen Therapy in Women: Another One of Yogi's Forks J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4091 - 4093. [Full Text] [PDF]
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N. Kajaia, H. Binder, R. Dittrich, P. G Oppelt, B. Flor, S. Cupisti, M. W Beckmann, and A. Mueller Low sex hormone-binding globulin as a predictive marker for insulin resistance in women with hyperandrogenic syndrome Eur. J. Endocrinol., October 1, 2007; 157(4): 499 - 507. [Abstract] [Full Text] [PDF]
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 G. D. Braunstein Gynecomastia N. Engl. J. Med., September 20, 2007; 357(12): 1229 - 1237. [Full Text] [PDF]
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 F. Z. Stanczyk, J. S. Lee, and R. J. Santen Standardization of Steroid Hormone Assays: Why, How, and When? Cancer Epidemiol. Biomarkers Prev., September 1, 2007; 16(9): 1713 - 1719. [Abstract] [Full Text] [PDF]
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A. Mueller, F. Kiesewetter, H. Binder, M. W. Beckmann, and R. Dittrich Long-Term Administration of Testosterone Undecanoate Every 3 Months for Testosterone Supplementation in Female-to-Male Transsexuals J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3470 - 3475. [Abstract] [Full Text] [PDF]
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A. Morgentaler Guideline for Male Testosterone Therapy: A Clinician's Perspective J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 416 - 417. [Full Text] [PDF]
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) and men (n = 50; •) obtained by 10 immunoassays and ID/GC-MS. The abcissa is the T concentration (nanomoles per liter) measured by ID/GC/MS. (To convert to nanograms per deciliter, multiply by 28.8.) The y-axis is the ratio of T concentration determined by immunoassay divided by T concentration determined by ID/GC-MS. The vertical dotted line separates the data for men and women. [Reprinted with permission from Taieb J, Mathian B, Millot F, Patricot MC, Mathieu E, Queyrel N, Lacroix I, Somma-Delpero C, Boudou P 2003 Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women, and children. Clin Chem 49:1381–1395 (