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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
Microdosing Enanthate
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<blockquote data-quote="madman" data-source="post: 214918" data-attributes="member: 13851"><p>T levels in healthy young males peak around age 19.</p><p></p><p>Even then everyone needs to keep in mind that such levels are not maintained 24/7 let alone it is far from common that a healthy young male is hitting a peak TT 1000+ ng/dL.</p><p></p><p>T levels of a healthy young male follow a diurnal 24 hr circadian rhythm and will start to rise gradually around 1-2 am reaching a short-lived peak between 6-8 am and start declining from 10 am well into the early evening reaching a nadir between 6-8 pm.</p><p></p><p>Fluctuations from peak--->trough would be around 20-25%.</p><p></p><p>When getting lab work done to see where natural endogenous levels sit testing should be done between 6-10 am as we want to test at the peak.</p><p></p><p>Just to be clear before everyone keeps on blaming this that and the other people need to be aware that the main reason for the lower reference range adopted from the more recent 2017 study comes down to <strong>harmonized reference ranges and standardized assays as testosterone concentrations were measured using a </strong><u><strong>higher-order liquid chromatography-tandem mass spectrometry method</strong></u><strong>.</strong></p><p><strong></strong></p><p><strong></strong></p><p><strong><em>*A large study of more than 9,000 men has established harmonized reference ranges for total testosterone in men that when applied to <u>assays that have been appropriately calibrated</u></em></strong><em> will effectively enable clinicians to make a correct diagnosis of hypogonadism, according to a new study published in the Endocrine Society's Journal of Clinical Endocrinology & Metabolism.</em></p><p></p><p></p><p></p><p></p><p><strong>Harmonized Reference Ranges for Circulating Testosterone Levels in Men of Four Cohort Studies in the United States and Europe (2016)</strong></p><p></p><p><em>Thomas G. Travison,1 Hubert W. Vesper,3 Eric Orwoll,4 Frederick Wu,5 Jean Marc Kaufman,6 Ying Wang,4 Bruno Lapauw,6 Tom Fiers,7 Alvin M. Matsumoto,8 and Shalender Bhasin2</em></p><p></p><p>[URL unfurl="true"]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460736/[/URL]</p><p></p><p></p><p><strong>Background:</strong> Reference ranges for testosterone are essential for making a diagnosis of hypogonadism in men.</p><p></p><p><strong>Objective: </strong>To establish <u>harmonized reference ranges for total testosterone in men</u> that can be applied across laboratories by <u>cross-calibrating assays to a reference method and standard</u>.</p><p></p><p><strong>Population:</strong> The 9054 community-dwelling men in cohort studies in the United States and Europe: <u>Framingham Heart Study</u>; European Male Aging Study; Osteoporotic Fractures in Men Study; and Male Sibling Study of Osteoporosis.</p><p></p><p><strong>Methods: </strong>Testosterone concentrations in 100 participants in each of the four cohorts were measured using a <u>reference method at the Centers for Disease Control and Prevention (CDC)</u>. Generalized additive models and Bland-Altman analyses supported the use of normalizing equations for transformation between cohort-specific and CDC values. <u>Normalizing equations, generated using Passing-Bablok regression, were used to generate harmonized values, which were used to derive standardized, age-specific reference ranges</u>.</p><p></p><p><strong>Results:</strong> <u>Harmonization procedure reduced intercohort variation between testosterone measurements in men of similar ages</u>. <u>In healthy non-obese men, 19 to 39 years, harmonized 2.5th, 5th, 50th, 95th, and 97.5th percentile values were 264, 303, 531, 852, and 916 ng/dL, respectively</u>. Age-specific harmonized testosterone concentrations in nonobese men were similar across cohorts and greater than in all men.</p><p></p><p><strong>Conclusion:<em> Harmonized normal range in a healthy nonobese population of European and American men, 19 to 39 years, is 264 to 916 ng/dL. <u>A substantial proportion of intercohort variation in testosterone levels is due to assay differences</u>. <u>These data demonstrate the feasibility of generating harmonized reference ranges for testosterone that can be applied to assays, which have been calibrated to a reference method and calibrator</u>.</em></strong></p><p></p><p></p><p></p><p></p><p><em>The reference ranges provide the basis for differentiating low from normal testosterone levels, and are, therefore, essential for making the diagnosis of hypogonadism. <strong>We have published reference ranges for circulating testosterone levels generated in healthy nonobese men who were participants in the Framingham Heart Study (FHS) (4); similar data have been published in other populations (5–11). </strong>However, an important unresolved question is whether the reference ranges generated in one population of men can be applied more broadly to men in other geographic regions and in other populations. <strong>The distribution of testosterone concentrations could vary in men from different regions due to interassay or interlaboratory differences, or biological or environmental factors.</strong></em></p><p><em></em></p><p><em>The objective of this initiative of the Endocrine Society was to compare the distribution of total testosterone concentrations in epidemiologic studies that included men from different geographic regions of the United States and Europe and to generate consensus reference ranges for total testosterone levels in men. <strong>We anticipated that, notwithstanding the substantial interindividual variation in testosterone levels observed within each cohort, there would also be significant and correctable variation in mean testosterone levels between cohorts owing specifically to differences in measurement technology. <u>We sought to minimize the influence of these systematic differences by harmonizing all measurements to a higher-order standard prior to the estimation of reference ranges</u>.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>Accordingly, serum testosterone levels were measured in male participants of four epidemiologic studies: the FHS</strong>, the European Male Aging Study (EMAS), the Osteoporotic Fractures in Men Study (MrOS), and the Sibling Study of Osteoporosis (SIBLOS). <strong>Because different assays were used for measuring testosterone levels in these four epidemiologic studies and because these assays used different calibrators, the assays were <u>cross calibrated centrally by measuring testosterone levels in serum samples from a subset of men in each cohort in the Centers for Disease Control and Prevention (CDC) Clinical Reference Laboratory using an assay calibrated with higher-order reference materials and using serum-based reference materials as additional accuracy controls</u>.</strong> </em></p><p><em></em></p><p><em><strong>*By comparing these new CDC-derived values with the original values obtained on these men from each cohort, we developed normalizing equations permitting translation from the original cohort-specific measurements to the CDC standard, and then applied them to the full sample of values in each cohort.</strong></em></p><p><em></em></p><p><em>Because testosterone levels decline with advancing age, we first generated reference ranges in healthy nonobese young men, 19 to 39 years, as this approach based on limits derived in a healthy young population has been favored historically for analytes that exhibit clinically meaningful age-related trends, such as estradiol and bone mineral density. <strong>Because of the well-known effect of obesity on testosterone levels and on age-related change in testosterone levels, we present age-adjusted reference ranges in nonobese men, and additionally for all men, by decades of age.</strong></em></p><p></p><p></p><p></p><p></p><p><strong>General approach </strong></p><p></p><p><em>First, fasting morning serum samples obtained from 100 men from each of the four cohorts, in which testosterone levels had previously been assayed locally, were transported to the central laboratory at the CDC. These 100 men with previous assay results from the local laboratory were chosen at random to approximate the distribution of age and other factors within each of the four cohorts. </em><strong><em>At CDC, testosterone concentrations were measured on each sample using a higher-order (a reference method against which other methods are compared) liquid chromatography-tandem mass spectrometry (LC-MS/MS) method under the supervision of Dr. Hubert Vesper.</em></strong><em> We then developed transformational equations for each study describing the relationship between the 100 local and 100 central measurements, providing an estimate of the systematic variation in local measurements from the reference standard. </em><strong><em>These normalizing equations were applied to all testosterone levels measured in each of the four cohorts to generate harmonized values. These harmonized measurements were in turn used to derive standardized, age-specific reference ranges in each of the four cohorts and overall.</em></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>FHS </strong></p><p></p><p><em>The original FHS cohort was established in 1948 by recruiting 5209 men and women between the ages of 30 and 62 from Framingham, Massachusetts. In 1971, the study enrolled 5124 of the original participants’ adult children and their spouses, who constituted the Second Generation Cohort (Generation 2). The Generation 2 examination 7 was attended by 1625 men between 1998 and 2002. Exclusion of men with prostate cancer undergoing androgen deprivation therapy (n = 8), men receiving testosterone therapy, and men with missing testosterone data (n = 158) resulted in a sample of 1459 for Generation 2.</em></p><p><em></em></p><p><em><strong>A Third Generation Cohort (4095 children of Generation 2, referred to as Generation 3) was established from 2002 to 2005 (14)</strong> <strong>(<a href="http://nhbli.nih.gov/about/framingham" target="_blank">http://nhbli.nih.gov/about/framingham</a>). </strong>Of the 1912 men who attended the first Generation 3 examination in 2002 to 2005, 1893 had total testosterone measurements, and 962 were #40 years, among whom 456 men of Generation 3 were free of cancer, cardiovascular disease, diabetes mellitus, hypertension, hypercholesterolemia, and obesity [body mass index (BMI) .30 kg/m2 ] and constituted the reference sample. The men who were receiving androgen deprivation therapy or had undergone orchiectomy for prostate cancer or were taking testosterone were excluded.</em></p><p><em></em></p><p><em><strong>The FHS combined sample was created by combining Generation 2 and Generation 3 samples.</strong> Generation 2 examination 7 was attended by 1625 men between 1998 and 2002. Exclusion of men with prostate cancer undergoing androgen deprivation therapy (n = 8), men receiving testosterone therapy, and men with missing testosterone data (n = 158) resulted in a sample of 1459 for Generation 2.<strong> This sample of 3352 men (1459 men in Generation 2 plus 1893 men in Generation 3) constituted the FHS combined sample.</strong></em></p><p></p><p></p><p></p><p></p><p><strong>Generation of reference ranges in healthy, nonobese (BMI <30 kg/m2 ) young men</strong></p><p></p><p><em>First, we selected men, 19 to 39 years, who were nonobese (BMI,<30 kg/m2 ) and free of major comorbidities, as described (4). Because men,<40 years were available only in the FHS and SIBLOS studies, data for 1185 men meeting these criteria from these cohorts were included in this analysis.</em></p><p></p><p><strong>Age-specific reference ranges in nonobese men</strong></p><p></p><p><em>We computed reference ranges for individuals with BMI,<30 kg/m2 by decades of age (19 to 39, 40 to 49, 50 to 59, 60 to 69, 70 to 79, and 80 to 99 years). There were 6933 men from the four cohorts meeting this BMI criterion. The analyses were first performed within each cohort, and then the cohorts were combined to derive model-based estimates of age trends in population quantiles.</em></p><p><em></em></p><p><em></em></p><p><em></em></p><p><em></em></p><p><em><strong>*Table 4 provides age-specific estimates of the percentiles of total testosterone distribution derived from all studies combined, after harmonization, using constrained quantile regression models.</strong> As is the case with the exploratory estimates described in Table 3, we observed age-related decreases in concentrations at the lower end of the distributions, whereas the upper centiles were largely stable across the age groups. <strong>Thus, among nonobese men, the age-specific 95th percentile estimates lie in a tight range (839 to 850 ng/dL), whereas the 5th percentile estimates vary more substantially, ranging from 304 in men 19 to 39 years of age to 252 in those 70 to 79 and 218 in those 80 and above.</strong></em></p><p></p><p>[ATTACH=full]19015[/ATTACH]</p><p></p><p></p><p></p><p></p><p><strong>Discussion </strong></p><p></p><p><em><strong>These data show that the cross-calibration of assays using a higher-order standard and a higher-order assay in a central laboratory provides a substantial reduction in intercohort variation.</strong> This suggests that measurement variation contributes to the previously observed variation in mean testosterone levels among epidemiological cohorts from different geographic regions, the substantial interindividual variation in hormone levels within any cohort notwithstanding. <strong>The distribution of harmonized total testosterone values in healthy nonobese young men was very similar between the FHS Generation 3 and the SIBLOS cohorts—2 geographically distinct cohorts. The <u>2.5th</u>, 5th, 50th, 95th, and <u>97.5th</u> percentile values in healthy nonobese young men were <u>264</u>, 303, 531, 852, and <u>916 ng/dL</u>, respectively (Table 2). </strong></em></p><p><em><strong></strong></em></p><p><em><strong>*We conclude that <u>standardized hormone measurements calibrated to a higher-order benchmark, such as that offered by the CDC Clinical Reference Laboratory, provide a rational and feasible approach to generating harmonized reference ranges for testosterone and possibly other analytes</u>.</strong></em></p><p><em></em></p><p><em></em></p><p><em></em></p><p><em></em></p><p><em>*The data reported in this work illustrate the promise and feasibility of generating reference ranges using harmonized values that can be applied across different geographic regions of the world to <strong>CDC-certified laboratories that use a common calibrator</strong></em><strong><em>. Such calibrators for testosterone and some other analytes are now available from the National Institute of Standards and Technologies</em></strong></p><p></p><p></p><p></p><p></p><p><em><strong>*In summary, these data demonstrate the feasibility and potential value of generating harmonized reference ranges for testosterone concentrations, whose serum total testosterone concentrations have been measured in a CDC-certified laboratory.</strong> <strong>There was a remarkable concordance in age-adjusted harmonized testosterone levels among men in four geographically distinct cohorts, suggesting that intercohort variation may be influenced by interassay variation. <u>Further studies of the distribution of testosterone concentrations in other racial and ethnic groups and in populations in other regions of the world are needed to demonstrate the applicability of these ranges to broader populations of men in different regions of the United States and the world</u>.</strong></em></p><p></p><p></p><p></p><p></p><p></p><p>Also, keep in mind that the authors of the more recent 2017 study were the same ones who contributed to the previously published reference ranges taken from the 2011 study.</p><p></p><p><em><strong>*We have published reference ranges for circulating testosterone levels generated in healthy nonobese men who were participants in the Framingham Heart Study (FHS) (4)</strong></em></p><p></p><p></p><p><strong>Reference Ranges for Testosterone in Men Generated Using Liquid Chromatography-Tandem Mass Spectrometry in a Community-Based Sample of Healthy Nonobese Young Men in the Framingham Heart Study and Applied to Three Geographically Distinct Cohorts (2011)</strong></p><p></p><p><em><u>Shalender Bhasin</u>, Michael Pencina, Guneet Kaur Jasuja, <u>Thomas G. Travison</u>, Andrea Coviello, <u>Eric Orwoll</u>,* <u>Patty Y. Wang</u>,* Carrie Nielson,* <u>Frederick Wu</u>,* Abdelouahid Tajar,* Fernand Labrie, <u>Hubert Vesper</u>, Anqi Zhang, Jagadish Ulloor, Ravinder Singh, Ralph D’Agostino, and Ramachandran S. Vasan</em></p><p></p><p>[URL unfurl="true"]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146796/[/URL]</p><p></p><p></p><p><strong>TABLE 3. Distribution of total and free testosterone in the FHS reference sample (n=456)</strong></p><p><strong></strong></p><p><strong>TT 348.3 - 1196.6 ng/dL (2.5/97.5)</strong></p><p>[ATTACH=full]19017[/ATTACH]</p><p></p><p></p><p></p><p></p><p></p><p><strong>Harmonized Reference Ranges for Circulating Testosterone Levels in Men of Four Cohort Studies in the United States and Europe (2016)</strong></p><p></p><p><em>Thomas G. Travison,1 Hubert W. Vesper,3 Eric Orwoll,4 Frederick Wu,5 Jean Marc Kaufman,6 Ying Wang,4 Bruno Lapauw,6 Tom Fiers,7 Alvin M. Matsumoto,8 and Shalender Bhasin2</em></p><p></p><p><strong>Table 4. Model-Based Estimates of Population Centiles for Total Testosterone Concentrations (ng/dL) Based on Data From NonobeseMen (N = 6933) and in All Men (N = 9054) in the <u>Four Harmonized Cohorts</u></strong></p><p><strong></strong></p><p><strong>All nonobese men (age 19-39) TT 267-929 ng/dL (2.5/97.5)</strong></p><p>[ATTACH=full]19016[/ATTACH]</p><p></p><p></p><p></p><p></p><p></p><p></p><p><strong>Q&A TESTOSTERONE REFERENCE INTERVAL CHANGES (ADULT MALES) (2017)</strong></p><p><strong></strong></p><p><strong>1. Why is Labcorp changing the testosterone reference interval?</strong></p><p></p><p>A: <em>Labcorp is changing to the recently standardized reference interval for adult males based upon <strong>testosterone assays standardized to the <u>CDC reference method</u>. This change was driven by the consensus effort for accurate testosterone testing,</strong> which was endorsed by a group of professional associations, government agencies, and commercial entities in 20210.</em></p><p></p><p><strong><em>One of the objectives outlined within the consensus statement was to establish standardized testosterone reference intervals by age and gender.</em></strong><em> Travison et al. published a population-based study at the beginning of 2017 which:</em></p><p></p><p>*<em>Evaluated more than 9,000 adult male patients from different geographic regions of the United States and Europe.</em></p><p></p><p>*<em>Included 1,185 adult males younger than 40 years of age, with a BMI less than 30.</em></p><p></p><p><strong><em>*Utilized testosterone assays harmonized to the CDC reference method.</em></strong></p><p></p><p><em>*Standardized testosterone reference interval for nonobese adult males (19-39 years of age, BMI <30) was calculated as 264-916 ng/dL.</em></p><p></p><p></p><p><strong>2. Why is Labcorp's reference interval changing to a lower numeric range?</strong></p><p></p><p>A: <em><strong>Labcorp's previous reference interval was adopted from a 2011 study that included a population of lean healthy males and utilized a testosterone LC/MS-MS assay <u>prior to the introduction of the CDC standardization protocol</u>.</strong> <strong><u>The previous reference interval was based on the Framingham Heart Study Population analyzed by Bhasin et al. and was the only comprehensive total testosterone reference interval study available at that point in time</u>.</strong> <strong>Labcorp adopted this reference interval for testosterone result interpretation and reporting.</strong></em></p><p></p><p><strong><em>In early 2017, Travison et al. demonstrated that obesity is directly associated with lower testosterone levels in male patients, and the new standardized reference interval established included adult males between 19-39 years old with a BMI less than 30. The lower numeric range in the standardized reference interval <u>reflects a difference in average subjects with higher BMIs as well as harmonization to the CDC reference method</u>.</em></strong></p><p></p><p></p><p></p><p></p><p>2011 study: <strong>TT <u>348.3 - 1196.6 ng/dL</u> (2.5/97.5)</strong></p><p>2016 study: <strong>TT All nonobese men (age 19-39) <u>TT 267-929 ng/dL</u> (2.5/97.5)</strong></p><p></p><p>2011 study: <strong>testosterone LC/MS-MS assay</strong></p><p>2016 study:<strong> testosterone assays standardized to the CDC reference method (higher-order liquid chromatography-tandem mass spectrometry method)</strong></p><p></p><p></p><p></p><p>Labcorp: pre-2017<strong> TT 348-1197 ng/dL---> </strong>July 2017<strong> TT 264-916 ng/dL</strong></p><p>[ATTACH=full]19018[/ATTACH]</p></blockquote><p></p>
[QUOTE="madman, post: 214918, member: 13851"] T levels in healthy young males peak around age 19. Even then everyone needs to keep in mind that such levels are not maintained 24/7 let alone it is far from common that a healthy young male is hitting a peak TT 1000+ ng/dL. T levels of a healthy young male follow a diurnal 24 hr circadian rhythm and will start to rise gradually around 1-2 am reaching a short-lived peak between 6-8 am and start declining from 10 am well into the early evening reaching a nadir between 6-8 pm. Fluctuations from peak--->trough would be around 20-25%. When getting lab work done to see where natural endogenous levels sit testing should be done between 6-10 am as we want to test at the peak. Just to be clear before everyone keeps on blaming this that and the other people need to be aware that the main reason for the lower reference range adopted from the more recent 2017 study comes down to [B]harmonized reference ranges and standardized assays as testosterone concentrations were measured using a [/B][U][B]higher-order liquid chromatography-tandem mass spectrometry method[/B][/U][B]. [I]*A large study of more than 9,000 men has established harmonized reference ranges for total testosterone in men that when applied to [U]assays that have been appropriately calibrated[/U][/I][/B][I] will effectively enable clinicians to make a correct diagnosis of hypogonadism, according to a new study published in the Endocrine Society's Journal of Clinical Endocrinology & Metabolism.[/I] [B]Harmonized Reference Ranges for Circulating Testosterone Levels in Men of Four Cohort Studies in the United States and Europe (2016)[/B] [I]Thomas G. Travison,1 Hubert W. Vesper,3 Eric Orwoll,4 Frederick Wu,5 Jean Marc Kaufman,6 Ying Wang,4 Bruno Lapauw,6 Tom Fiers,7 Alvin M. Matsumoto,8 and Shalender Bhasin2[/I] [URL unfurl="true"]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460736/[/URL] [B]Background:[/B] Reference ranges for testosterone are essential for making a diagnosis of hypogonadism in men. [B]Objective: [/B]To establish [U]harmonized reference ranges for total testosterone in men[/U] that can be applied across laboratories by [U]cross-calibrating assays to a reference method and standard[/U]. [B]Population:[/B] The 9054 community-dwelling men in cohort studies in the United States and Europe: [U]Framingham Heart Study[/U]; European Male Aging Study; Osteoporotic Fractures in Men Study; and Male Sibling Study of Osteoporosis. [B]Methods: [/B]Testosterone concentrations in 100 participants in each of the four cohorts were measured using a [U]reference method at the Centers for Disease Control and Prevention (CDC)[/U]. Generalized additive models and Bland-Altman analyses supported the use of normalizing equations for transformation between cohort-specific and CDC values. [U]Normalizing equations, generated using Passing-Bablok regression, were used to generate harmonized values, which were used to derive standardized, age-specific reference ranges[/U]. [B]Results:[/B] [U]Harmonization procedure reduced intercohort variation between testosterone measurements in men of similar ages[/U]. [U]In healthy non-obese men, 19 to 39 years, harmonized 2.5th, 5th, 50th, 95th, and 97.5th percentile values were 264, 303, 531, 852, and 916 ng/dL, respectively[/U]. Age-specific harmonized testosterone concentrations in nonobese men were similar across cohorts and greater than in all men. [B]Conclusion:[I] Harmonized normal range in a healthy nonobese population of European and American men, 19 to 39 years, is 264 to 916 ng/dL. [U]A substantial proportion of intercohort variation in testosterone levels is due to assay differences[/U]. [U]These data demonstrate the feasibility of generating harmonized reference ranges for testosterone that can be applied to assays, which have been calibrated to a reference method and calibrator[/U].[/I][/B] [I]The reference ranges provide the basis for differentiating low from normal testosterone levels, and are, therefore, essential for making the diagnosis of hypogonadism. [B]We have published reference ranges for circulating testosterone levels generated in healthy nonobese men who were participants in the Framingham Heart Study (FHS) (4); similar data have been published in other populations (5–11). [/B]However, an important unresolved question is whether the reference ranges generated in one population of men can be applied more broadly to men in other geographic regions and in other populations. [B]The distribution of testosterone concentrations could vary in men from different regions due to interassay or interlaboratory differences, or biological or environmental factors.[/B] The objective of this initiative of the Endocrine Society was to compare the distribution of total testosterone concentrations in epidemiologic studies that included men from different geographic regions of the United States and Europe and to generate consensus reference ranges for total testosterone levels in men. [B]We anticipated that, notwithstanding the substantial interindividual variation in testosterone levels observed within each cohort, there would also be significant and correctable variation in mean testosterone levels between cohorts owing specifically to differences in measurement technology. [U]We sought to minimize the influence of these systematic differences by harmonizing all measurements to a higher-order standard prior to the estimation of reference ranges[/U]. Accordingly, serum testosterone levels were measured in male participants of four epidemiologic studies: the FHS[/B], the European Male Aging Study (EMAS), the Osteoporotic Fractures in Men Study (MrOS), and the Sibling Study of Osteoporosis (SIBLOS). [B]Because different assays were used for measuring testosterone levels in these four epidemiologic studies and because these assays used different calibrators, the assays were [U]cross calibrated centrally by measuring testosterone levels in serum samples from a subset of men in each cohort in the Centers for Disease Control and Prevention (CDC) Clinical Reference Laboratory using an assay calibrated with higher-order reference materials and using serum-based reference materials as additional accuracy controls[/U].[/B] [B]*By comparing these new CDC-derived values with the original values obtained on these men from each cohort, we developed normalizing equations permitting translation from the original cohort-specific measurements to the CDC standard, and then applied them to the full sample of values in each cohort.[/B] Because testosterone levels decline with advancing age, we first generated reference ranges in healthy nonobese young men, 19 to 39 years, as this approach based on limits derived in a healthy young population has been favored historically for analytes that exhibit clinically meaningful age-related trends, such as estradiol and bone mineral density. [B]Because of the well-known effect of obesity on testosterone levels and on age-related change in testosterone levels, we present age-adjusted reference ranges in nonobese men, and additionally for all men, by decades of age.[/B][/I] [B]General approach [/B] [I]First, fasting morning serum samples obtained from 100 men from each of the four cohorts, in which testosterone levels had previously been assayed locally, were transported to the central laboratory at the CDC. These 100 men with previous assay results from the local laboratory were chosen at random to approximate the distribution of age and other factors within each of the four cohorts. [/I][B][I]At CDC, testosterone concentrations were measured on each sample using a higher-order (a reference method against which other methods are compared) liquid chromatography-tandem mass spectrometry (LC-MS/MS) method under the supervision of Dr. Hubert Vesper.[/I][/B][I] We then developed transformational equations for each study describing the relationship between the 100 local and 100 central measurements, providing an estimate of the systematic variation in local measurements from the reference standard. [/I][B][I]These normalizing equations were applied to all testosterone levels measured in each of the four cohorts to generate harmonized values. These harmonized measurements were in turn used to derive standardized, age-specific reference ranges in each of the four cohorts and overall.[/I] FHS [/B] [I]The original FHS cohort was established in 1948 by recruiting 5209 men and women between the ages of 30 and 62 from Framingham, Massachusetts. In 1971, the study enrolled 5124 of the original participants’ adult children and their spouses, who constituted the Second Generation Cohort (Generation 2). The Generation 2 examination 7 was attended by 1625 men between 1998 and 2002. Exclusion of men with prostate cancer undergoing androgen deprivation therapy (n = 8), men receiving testosterone therapy, and men with missing testosterone data (n = 158) resulted in a sample of 1459 for Generation 2. [B]A Third Generation Cohort (4095 children of Generation 2, referred to as Generation 3) was established from 2002 to 2005 (14)[/B] [B]([URL]http://nhbli.nih.gov/about/framingham[/URL]). [/B]Of the 1912 men who attended the first Generation 3 examination in 2002 to 2005, 1893 had total testosterone measurements, and 962 were #40 years, among whom 456 men of Generation 3 were free of cancer, cardiovascular disease, diabetes mellitus, hypertension, hypercholesterolemia, and obesity [body mass index (BMI) .30 kg/m2 ] and constituted the reference sample. The men who were receiving androgen deprivation therapy or had undergone orchiectomy for prostate cancer or were taking testosterone were excluded. [B]The FHS combined sample was created by combining Generation 2 and Generation 3 samples.[/B] Generation 2 examination 7 was attended by 1625 men between 1998 and 2002. Exclusion of men with prostate cancer undergoing androgen deprivation therapy (n = 8), men receiving testosterone therapy, and men with missing testosterone data (n = 158) resulted in a sample of 1459 for Generation 2.[B] This sample of 3352 men (1459 men in Generation 2 plus 1893 men in Generation 3) constituted the FHS combined sample.[/B][/I] [B]Generation of reference ranges in healthy, nonobese (BMI <30 kg/m2 ) young men[/B] [I]First, we selected men, 19 to 39 years, who were nonobese (BMI,<30 kg/m2 ) and free of major comorbidities, as described (4). Because men,<40 years were available only in the FHS and SIBLOS studies, data for 1185 men meeting these criteria from these cohorts were included in this analysis.[/I] [B]Age-specific reference ranges in nonobese men[/B] [I]We computed reference ranges for individuals with BMI,<30 kg/m2 by decades of age (19 to 39, 40 to 49, 50 to 59, 60 to 69, 70 to 79, and 80 to 99 years). There were 6933 men from the four cohorts meeting this BMI criterion. The analyses were first performed within each cohort, and then the cohorts were combined to derive model-based estimates of age trends in population quantiles. [B]*Table 4 provides age-specific estimates of the percentiles of total testosterone distribution derived from all studies combined, after harmonization, using constrained quantile regression models.[/B] As is the case with the exploratory estimates described in Table 3, we observed age-related decreases in concentrations at the lower end of the distributions, whereas the upper centiles were largely stable across the age groups. [B]Thus, among nonobese men, the age-specific 95th percentile estimates lie in a tight range (839 to 850 ng/dL), whereas the 5th percentile estimates vary more substantially, ranging from 304 in men 19 to 39 years of age to 252 in those 70 to 79 and 218 in those 80 and above.[/B][/I] [ATTACH type="full" alt="Screenshot (10321).png"]19015[/ATTACH] [B]Discussion [/B] [I][B]These data show that the cross-calibration of assays using a higher-order standard and a higher-order assay in a central laboratory provides a substantial reduction in intercohort variation.[/B] This suggests that measurement variation contributes to the previously observed variation in mean testosterone levels among epidemiological cohorts from different geographic regions, the substantial interindividual variation in hormone levels within any cohort notwithstanding. [B]The distribution of harmonized total testosterone values in healthy nonobese young men was very similar between the FHS Generation 3 and the SIBLOS cohorts—2 geographically distinct cohorts. The [U]2.5th[/U], 5th, 50th, 95th, and [U]97.5th[/U] percentile values in healthy nonobese young men were [U]264[/U], 303, 531, 852, and [U]916 ng/dL[/U], respectively (Table 2). *We conclude that [U]standardized hormone measurements calibrated to a higher-order benchmark, such as that offered by the CDC Clinical Reference Laboratory, provide a rational and feasible approach to generating harmonized reference ranges for testosterone and possibly other analytes[/U].[/B] *The data reported in this work illustrate the promise and feasibility of generating reference ranges using harmonized values that can be applied across different geographic regions of the world to [B]CDC-certified laboratories that use a common calibrator[/B][/I][B][I]. Such calibrators for testosterone and some other analytes are now available from the National Institute of Standards and Technologies[/I][/B] [I][B]*In summary, these data demonstrate the feasibility and potential value of generating harmonized reference ranges for testosterone concentrations, whose serum total testosterone concentrations have been measured in a CDC-certified laboratory.[/B] [B]There was a remarkable concordance in age-adjusted harmonized testosterone levels among men in four geographically distinct cohorts, suggesting that intercohort variation may be influenced by interassay variation. [U]Further studies of the distribution of testosterone concentrations in other racial and ethnic groups and in populations in other regions of the world are needed to demonstrate the applicability of these ranges to broader populations of men in different regions of the United States and the world[/U].[/B][/I] Also, keep in mind that the authors of the more recent 2017 study were the same ones who contributed to the previously published reference ranges taken from the 2011 study. [I][B]*We have published reference ranges for circulating testosterone levels generated in healthy nonobese men who were participants in the Framingham Heart Study (FHS) (4)[/B][/I] [B]Reference Ranges for Testosterone in Men Generated Using Liquid Chromatography-Tandem Mass Spectrometry in a Community-Based Sample of Healthy Nonobese Young Men in the Framingham Heart Study and Applied to Three Geographically Distinct Cohorts (2011)[/B] [I][U]Shalender Bhasin[/U], Michael Pencina, Guneet Kaur Jasuja, [U]Thomas G. Travison[/U], Andrea Coviello, [U]Eric Orwoll[/U],* [U]Patty Y. Wang[/U],* Carrie Nielson,* [U]Frederick Wu[/U],* Abdelouahid Tajar,* Fernand Labrie, [U]Hubert Vesper[/U], Anqi Zhang, Jagadish Ulloor, Ravinder Singh, Ralph D’Agostino, and Ramachandran S. Vasan[/I] [URL unfurl="true"]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146796/[/URL] [B]TABLE 3. Distribution of total and free testosterone in the FHS reference sample (n=456) TT 348.3 - 1196.6 ng/dL (2.5/97.5)[/B] [ATTACH type="full" alt="Screenshot (10318).png"]19017[/ATTACH] [B]Harmonized Reference Ranges for Circulating Testosterone Levels in Men of Four Cohort Studies in the United States and Europe (2016)[/B] [I]Thomas G. Travison,1 Hubert W. Vesper,3 Eric Orwoll,4 Frederick Wu,5 Jean Marc Kaufman,6 Ying Wang,4 Bruno Lapauw,6 Tom Fiers,7 Alvin M. Matsumoto,8 and Shalender Bhasin2[/I] [B]Table 4. Model-Based Estimates of Population Centiles for Total Testosterone Concentrations (ng/dL) Based on Data From NonobeseMen (N = 6933) and in All Men (N = 9054) in the [U]Four Harmonized Cohorts[/U] All nonobese men (age 19-39) TT 267-929 ng/dL (2.5/97.5)[/B] [ATTACH type="full" alt="Screenshot (10321).png"]19016[/ATTACH] [B]Q&A TESTOSTERONE REFERENCE INTERVAL CHANGES (ADULT MALES) (2017) 1. Why is Labcorp changing the testosterone reference interval?[/B] A: [I]Labcorp is changing to the recently standardized reference interval for adult males based upon [B]testosterone assays standardized to the [U]CDC reference method[/U]. This change was driven by the consensus effort for accurate testosterone testing,[/B] which was endorsed by a group of professional associations, government agencies, and commercial entities in 20210.[/I] [B][I]One of the objectives outlined within the consensus statement was to establish standardized testosterone reference intervals by age and gender.[/I][/B][I] Travison et al. published a population-based study at the beginning of 2017 which:[/I] *[I]Evaluated more than 9,000 adult male patients from different geographic regions of the United States and Europe.[/I] *[I]Included 1,185 adult males younger than 40 years of age, with a BMI less than 30.[/I] [B][I]*Utilized testosterone assays harmonized to the CDC reference method.[/I][/B] [I]*Standardized testosterone reference interval for nonobese adult males (19-39 years of age, BMI <30) was calculated as 264-916 ng/dL.[/I] [B]2. Why is Labcorp's reference interval changing to a lower numeric range?[/B] A: [I][B]Labcorp's previous reference interval was adopted from a 2011 study that included a population of lean healthy males and utilized a testosterone LC/MS-MS assay [U]prior to the introduction of the CDC standardization protocol[/U].[/B] [B][U]The previous reference interval was based on the Framingham Heart Study Population analyzed by Bhasin et al. and was the only comprehensive total testosterone reference interval study available at that point in time[/U].[/B] [B]Labcorp adopted this reference interval for testosterone result interpretation and reporting.[/B][/I] [B][I]In early 2017, Travison et al. demonstrated that obesity is directly associated with lower testosterone levels in male patients, and the new standardized reference interval established included adult males between 19-39 years old with a BMI less than 30. The lower numeric range in the standardized reference interval [U]reflects a difference in average subjects with higher BMIs as well as harmonization to the CDC reference method[/U].[/I][/B] 2011 study: [B]TT [U]348.3 - 1196.6 ng/dL[/U] (2.5/97.5)[/B] 2016 study: [B]TT All nonobese men (age 19-39) [U]TT 267-929 ng/dL[/U] (2.5/97.5)[/B] 2011 study: [B]testosterone LC/MS-MS assay[/B] 2016 study:[B] testosterone assays standardized to the CDC reference method (higher-order liquid chromatography-tandem mass spectrometry method)[/B] Labcorp: pre-2017[B] TT 348-1197 ng/dL---> [/B]July 2017[B] TT 264-916 ng/dL[/B] [ATTACH type="full" alt="Screenshot (10320).png"]19018[/ATTACH] [/QUOTE]
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