madman
Super Moderator
What Is a Normal Testosterone Level for Young Men? Rethinking the 300 ng/dL Cutoff for Testosterone Deficiency in Men 20-44 Years Old (2022)
Alex Zhu, Juan Andino, Stephanie Daignault-Newton, Zoey Chopra, Aruna Sarma, and James M. Dupree
Study Need and Importance: Testosterone reference ranges for older men are long established in the urological literature. However, few studies have examined testosterone levels in young men. As a result, clinicians have struggled to counsel and evaluate young men presenting with concerns about testosterone deficiency. Contributing to this struggle is the fact that testosterone levels decline with age, yet we use the same age-independent cutoffs to evaluate young men for testosterone deficiency as we do for older men. In response, we performed the first study evaluating population-based testosterone levels for younger men in the United States. We also used the 2018 American Urological Association guideline for testosterone deficiency definition of “normal testosterone” as the middle tertile of the population, to provide age-specific cutoffs for low testosterone levels in younger men.
What We Found: The mean total testosterone of men 20-44 years old was 466 ng/dL. Middle tertile, “normal” testosterone levels were 409-558 ng/dL (20-24 years old), 413-575 ng/dL (25-29 years old), 359-498 ng/dL (30-34 years old), 352e478 ng/dL (35-39 years old), and 350-473 ng/dL (40-44 years old). Age-specific cutoffs for low testosterone levels were 409, 413, 359, 352, and 350 ng/dL, respectively (see Figure).
Limitations: Our age-specific cutoffs for testosterone are modeled on the American Urological Association guideline definition that a normal testosterone level is within the middle tertile. However, no randomized controlled trials have been performed to select the middle tertile as a cutoff value. Additionally, our study is limited by some shortcomings of the National Health and Nutrition Examination Survey database. Namely, the National Health and Nutrition Examination Survey does not specifically query men for hypogonadal signs and symptoms, and only 1 serum testosterone value was obtained from each subject.
Interpretation for Patient Care: Clinicians should integrate age-specific cutoffs into the evaluation of younger men presenting with testosterone deficiency. Age-specific cutoffs will be useful in evaluating younger patients with hypogonadal symptoms who have historically been disqualified from treatment based on age-independent cutoffs.
Purpose: There is an age-related decline in male testosterone production. It is therefore surprising that young men are evaluated for testosterone deficiency with the same cutoff of 300 ng/dL that was developed from samples of older men. Our aim is to describe normative total testosterone levels and age-specific cutoffs for low testosterone levels in men 20 to 44 years old.
Materials and Methods: We analyzed the 2011-2016 National Health and Nutrition Examination Surveys, which survey nationally representative samples of United States residents. Men 20 to 44 years old with testosterone levels were included. Men on hormonal medications, with a history of testicular cancer or orchiectomy, and with afternoon/evening laboratory values were excluded. We separated men into 5-year intervals and evaluated the testosterone levels of each age group, and for all men 20 to 44 years old. We used the American Urological Association definition of a “normal testosterone level” (the “middle tertile”) to calculate age-specific cutoffs for low testosterone levels.
Results: Our final analytic cohort contained 1,486 men. Age-specific middle tertile levels were 409-558 ng/dL (20-24 years old), 413-575 ng/dL (25-29 years old), 359- 498 ng/dL (30-34 years old), 352-478 ng/dL (35-39 years old), and 350-473 ng/dL (40-44 years old). Age-specific cutoffs for low testosterone levels were 409, 413, 359, 352, and 350 ng/dL, respectively.
Conclusions: Diagnosis of testosterone deficiency has traditionally been performed in an age-indiscriminate manner. However, young men have different testosterone reference ranges than older men. Accordingly, age-specific normative values and cutoffs should be integrated into the evaluation of young men presenting with testosterone deficiency.
TESTOSTERONE deficiency, which is defined as a combination of low serum testosterone levels plus signs and symptoms of hypogonadism, affects 4.0 to 13.8 million1,2 men in the U.S. Although traditionally thought of as a disease affecting elderly men, young men are increasingly presenting with concerns related to testosterone deficiency. In addition, testosterone levels, sperm counts, and fertility have declined in young men over the past 2 decades.3 However, the diagnosis of testosterone deficiency in young men remains challenging. Whereas symptoms such as decreased libido or erectile dysfunction are common in older men, young men often present with less specific symptoms such as low energy and fatigue.4
Another significant challenge in evaluating young men for testosterone deficiency is uncertainty about what constitutes a “normal” testosterone level in these men. Testosterone levels decline with age,5 yet we historically have used the same age-independent cutoffs to evaluate young men as we use for older men. The American Urological Association (AUA) guideline suggests using a cutoff for low testosterone of 300 ng/dL when evaluating adult men.6 However, this age-independent 300 ng/dL cutoff has 3 problems for young men. First, this cutoff was derived from testosterone replacement trials that primarily studied men above the age of 45.6 Second, as described above, it is known that testosterone levels decline with age.5 Third, there are competing cutoffs reported in literature2,7 and from professional societies such as the American Association of Clinical Endocrinologists (200 ng/dL),8 Endocrine Society (264 ng/dL),9 British Society of Sexual Medicine (345 ng/dL),10 European Association of Urology (345 ng/dL),11 International Society of Sexual Medicine (350 ng/dL),12 and the International Society for Study of Aging Male (350 ng/ dL;13 Table 1). The 2018 AUA guideline for testosterone deficiency recognized our knowledge gap about normal testosterone levels for men of different ages and specifically called for the development of age-specific reference ranges for testosterone.6
DISCUSSION
In this study, we provide the first evaluation of normative, population-based testosterone levels for young men in the United States. We also used the 2018 AUA guideline’s definition of “normal testosterone” levels to provide the first age-specific cutoffs for low testosterone levels from a nationally representative population. These findings will provide valuable information that clinicians can use in the evaluation and management of young men presenting with concerns about testosterone deficiency.
Testosterone reference ranges for older men are long established in the urological literature.22 However, few studies have examined testosterone levels in young men. In an attempt to bridge this gap, the Endocrine Society commissioned a study in 2017 to evaluate testosterone reference ranges for young men.23 This study pooled morning testosterone samples from the Framingham Heart Study and Sibling Study of Osteoporosis and found that average testosterone levels for 19- to 39-year-old men were between 228 and 895 ng/dL.23 However, there are multiple issues with the makeup of the Framingham Heart Study and Sibling Study of Osteoporosis cohorts. The Framingham Heart Study was composed exclusively of sons and brothers from Framingham, Massachusetts consisted entirely of European Americans, and excluded patients with most comorbid conditions.24 The Sibling Study of Osteoporosis was similarly composed of 92% brothers who resided in Ghent, Belgium, and who were all Caucasian and healthy.25 Other studies evaluating testosterone levels in young men suffer from a similar lack of diversity in their study populations.26
Our study builds upon these previous attempts to evaluate normal testosterone levels in younger men by utilizing the strengths of the NHANES database to examine testosterone levels in a diverse, comorbid, and nationally representative population. Whereas previous studies examined “healthy, nonobese young men without major comorbidities,”23 our study includes all men regardless of comorbidities, as long as they were not on hormonal medications or had a history of testicular cancer or orchiectomy. Additionally, our cohort was selected from a weighted sample of U.S. counties, which is useful since testosterone levels can vary by 20% depending on the location of residence.27 Furthermore, men in our study were not from related families, and ethnic/racial subgroups were weighted and sampled to ensure a nationally representative result. This diversity is important because ethnic/racial heritage has been associated with differences in testosterone levels as well.28 Taken together, the intentional heterogeneity of our NHANES cohort may provide a more accurate representation of the normative testosterone levels for young men in the U.S., regardless of comorbidities, location, or ethnic/racial background
Our study has several limitations. First, our decision to use the 33rd percentile as a cutoff for low testosterone is based on the AUA guideline recommendation that normal testosterone lies within the middle tertile. No randomized control trials were performed to select the 33rd percentile as a cutoff value.
Nevertheless, the AUA guideline committee analyzed multiple population epidemiological studies to arrive at this suggested cutoff. Even if one were to choose a different cutoff, our age-specific normative testosterone ranges still provide young men and their physicians a framework for counseling (Table 3). Second, NHANES only obtained 1 serum testosterone value from each subject. Studies have shown that 30%-35% of men who are classified as hypogonadal based on a single low total testosterone subsequently have normal total testosterone levels over the next 24 hours. Thus, 2 low total testosterone values are recommended to confirm the diagnosis of low testosterone.29 The NHANES do not perform second blood draws, however, we believe the strengths of the NHANES data source outweigh this weakness. Third, the NHANES does not contain data about hypogonadal symptoms it only contains serum testosterone laboratory values. However, lab values are a key component of counseling for testosterone deficiency, and reference ranges are often questioned by young men in the clinic. Additionally, because NHANES does not ask about hypogonadal symptoms, our population invariably contained some men with symptomatic, clinical hypogonadism. Thus, the normative values we provide may underestimate the testosterone values for asymptomatic men. Nevertheless, patients with hypogonadal symptoms are present within the general population and their testosterone levels are part of the physiological range of testosterone levels for all men. Fourth, the NHANES does not provide information about bioavailable or free testosterone. Bioavailable or free testosterone are unable to be calculated due to a lack of data regarding sex hormone-binding globulin in the 2011 to 2012 NHANES data. Finally, we chose to use 5-year age intervals when creating our normative values to strike a balance between longer, 10-year intervals that have been used in other testosterone studies and narrower 1-year age intervals that could be more difficult to remember. Nevertheless, if clinicians needed wider or narrower age-based values, they could be derived from NHANES using the methods we described above.
These limitations notwithstanding, our findings have important implications for clinicians, patients, payers, and policymakers. Our age-specific cutoffs for low testosterone levels can help clinicians who have struggled with diagnosing testosterone deficiency in young men. In today’s age of personalized medicine, clinicians can now use age-specific testosterone levels to evaluate young men instead of relying on a “one size fits all” approach. For patients, we offer normative reference ranges that can be used to compare their testosterone levels to age-matched peers. Our cutoffs also benefit young men who experience hypogonadal symptoms but who have historically been disqualified from treatment based on the age-independent 300 ng/dL cutoff. Patients may also receive financial benefits from these cutoffs, as many insurance companies currently do not cover testosterone therapies if a man’s testosterone is >300 ng/dL. For payers and policymakers, these age-specific cutoffs may serve as evidence-based benchmarks to guide coverage decisions for the treatment of hypogonadism. Notably, young men in their reproductive years must understand that testosterone therapy can suppress spermatogenesis and must be pursued with caution if they are interested in current or future paternity.30
CONCLUSIONS
Our findings suggest that young men have different testosterone reference ranges than older men; the management of young men should accordingly reflect these differences. In particular, providers should question the use of an age-independent cutoff for young men and should integrate age-specific cutoffs into their evaluation of young men presenting with testosterone deficiency. Future research should correlate these age-specific cutoffs to hypogonadal symptoms and responses to treatment. Development of age-specific reference ranges and cutoffs for free testosterone and sex hormone-binding globulin may also be useful in the future management of young men with hypogonadism.
Alex Zhu, Juan Andino, Stephanie Daignault-Newton, Zoey Chopra, Aruna Sarma, and James M. Dupree
Study Need and Importance: Testosterone reference ranges for older men are long established in the urological literature. However, few studies have examined testosterone levels in young men. As a result, clinicians have struggled to counsel and evaluate young men presenting with concerns about testosterone deficiency. Contributing to this struggle is the fact that testosterone levels decline with age, yet we use the same age-independent cutoffs to evaluate young men for testosterone deficiency as we do for older men. In response, we performed the first study evaluating population-based testosterone levels for younger men in the United States. We also used the 2018 American Urological Association guideline for testosterone deficiency definition of “normal testosterone” as the middle tertile of the population, to provide age-specific cutoffs for low testosterone levels in younger men.
What We Found: The mean total testosterone of men 20-44 years old was 466 ng/dL. Middle tertile, “normal” testosterone levels were 409-558 ng/dL (20-24 years old), 413-575 ng/dL (25-29 years old), 359-498 ng/dL (30-34 years old), 352e478 ng/dL (35-39 years old), and 350-473 ng/dL (40-44 years old). Age-specific cutoffs for low testosterone levels were 409, 413, 359, 352, and 350 ng/dL, respectively (see Figure).
Limitations: Our age-specific cutoffs for testosterone are modeled on the American Urological Association guideline definition that a normal testosterone level is within the middle tertile. However, no randomized controlled trials have been performed to select the middle tertile as a cutoff value. Additionally, our study is limited by some shortcomings of the National Health and Nutrition Examination Survey database. Namely, the National Health and Nutrition Examination Survey does not specifically query men for hypogonadal signs and symptoms, and only 1 serum testosterone value was obtained from each subject.
Interpretation for Patient Care: Clinicians should integrate age-specific cutoffs into the evaluation of younger men presenting with testosterone deficiency. Age-specific cutoffs will be useful in evaluating younger patients with hypogonadal symptoms who have historically been disqualified from treatment based on age-independent cutoffs.
Purpose: There is an age-related decline in male testosterone production. It is therefore surprising that young men are evaluated for testosterone deficiency with the same cutoff of 300 ng/dL that was developed from samples of older men. Our aim is to describe normative total testosterone levels and age-specific cutoffs for low testosterone levels in men 20 to 44 years old.
Materials and Methods: We analyzed the 2011-2016 National Health and Nutrition Examination Surveys, which survey nationally representative samples of United States residents. Men 20 to 44 years old with testosterone levels were included. Men on hormonal medications, with a history of testicular cancer or orchiectomy, and with afternoon/evening laboratory values were excluded. We separated men into 5-year intervals and evaluated the testosterone levels of each age group, and for all men 20 to 44 years old. We used the American Urological Association definition of a “normal testosterone level” (the “middle tertile”) to calculate age-specific cutoffs for low testosterone levels.
Results: Our final analytic cohort contained 1,486 men. Age-specific middle tertile levels were 409-558 ng/dL (20-24 years old), 413-575 ng/dL (25-29 years old), 359- 498 ng/dL (30-34 years old), 352-478 ng/dL (35-39 years old), and 350-473 ng/dL (40-44 years old). Age-specific cutoffs for low testosterone levels were 409, 413, 359, 352, and 350 ng/dL, respectively.
Conclusions: Diagnosis of testosterone deficiency has traditionally been performed in an age-indiscriminate manner. However, young men have different testosterone reference ranges than older men. Accordingly, age-specific normative values and cutoffs should be integrated into the evaluation of young men presenting with testosterone deficiency.
TESTOSTERONE deficiency, which is defined as a combination of low serum testosterone levels plus signs and symptoms of hypogonadism, affects 4.0 to 13.8 million1,2 men in the U.S. Although traditionally thought of as a disease affecting elderly men, young men are increasingly presenting with concerns related to testosterone deficiency. In addition, testosterone levels, sperm counts, and fertility have declined in young men over the past 2 decades.3 However, the diagnosis of testosterone deficiency in young men remains challenging. Whereas symptoms such as decreased libido or erectile dysfunction are common in older men, young men often present with less specific symptoms such as low energy and fatigue.4
Another significant challenge in evaluating young men for testosterone deficiency is uncertainty about what constitutes a “normal” testosterone level in these men. Testosterone levels decline with age,5 yet we historically have used the same age-independent cutoffs to evaluate young men as we use for older men. The American Urological Association (AUA) guideline suggests using a cutoff for low testosterone of 300 ng/dL when evaluating adult men.6 However, this age-independent 300 ng/dL cutoff has 3 problems for young men. First, this cutoff was derived from testosterone replacement trials that primarily studied men above the age of 45.6 Second, as described above, it is known that testosterone levels decline with age.5 Third, there are competing cutoffs reported in literature2,7 and from professional societies such as the American Association of Clinical Endocrinologists (200 ng/dL),8 Endocrine Society (264 ng/dL),9 British Society of Sexual Medicine (345 ng/dL),10 European Association of Urology (345 ng/dL),11 International Society of Sexual Medicine (350 ng/dL),12 and the International Society for Study of Aging Male (350 ng/ dL;13 Table 1). The 2018 AUA guideline for testosterone deficiency recognized our knowledge gap about normal testosterone levels for men of different ages and specifically called for the development of age-specific reference ranges for testosterone.6
DISCUSSION
In this study, we provide the first evaluation of normative, population-based testosterone levels for young men in the United States. We also used the 2018 AUA guideline’s definition of “normal testosterone” levels to provide the first age-specific cutoffs for low testosterone levels from a nationally representative population. These findings will provide valuable information that clinicians can use in the evaluation and management of young men presenting with concerns about testosterone deficiency.
Testosterone reference ranges for older men are long established in the urological literature.22 However, few studies have examined testosterone levels in young men. In an attempt to bridge this gap, the Endocrine Society commissioned a study in 2017 to evaluate testosterone reference ranges for young men.23 This study pooled morning testosterone samples from the Framingham Heart Study and Sibling Study of Osteoporosis and found that average testosterone levels for 19- to 39-year-old men were between 228 and 895 ng/dL.23 However, there are multiple issues with the makeup of the Framingham Heart Study and Sibling Study of Osteoporosis cohorts. The Framingham Heart Study was composed exclusively of sons and brothers from Framingham, Massachusetts consisted entirely of European Americans, and excluded patients with most comorbid conditions.24 The Sibling Study of Osteoporosis was similarly composed of 92% brothers who resided in Ghent, Belgium, and who were all Caucasian and healthy.25 Other studies evaluating testosterone levels in young men suffer from a similar lack of diversity in their study populations.26
Our study builds upon these previous attempts to evaluate normal testosterone levels in younger men by utilizing the strengths of the NHANES database to examine testosterone levels in a diverse, comorbid, and nationally representative population. Whereas previous studies examined “healthy, nonobese young men without major comorbidities,”23 our study includes all men regardless of comorbidities, as long as they were not on hormonal medications or had a history of testicular cancer or orchiectomy. Additionally, our cohort was selected from a weighted sample of U.S. counties, which is useful since testosterone levels can vary by 20% depending on the location of residence.27 Furthermore, men in our study were not from related families, and ethnic/racial subgroups were weighted and sampled to ensure a nationally representative result. This diversity is important because ethnic/racial heritage has been associated with differences in testosterone levels as well.28 Taken together, the intentional heterogeneity of our NHANES cohort may provide a more accurate representation of the normative testosterone levels for young men in the U.S., regardless of comorbidities, location, or ethnic/racial background
Our study has several limitations. First, our decision to use the 33rd percentile as a cutoff for low testosterone is based on the AUA guideline recommendation that normal testosterone lies within the middle tertile. No randomized control trials were performed to select the 33rd percentile as a cutoff value.
Nevertheless, the AUA guideline committee analyzed multiple population epidemiological studies to arrive at this suggested cutoff. Even if one were to choose a different cutoff, our age-specific normative testosterone ranges still provide young men and their physicians a framework for counseling (Table 3). Second, NHANES only obtained 1 serum testosterone value from each subject. Studies have shown that 30%-35% of men who are classified as hypogonadal based on a single low total testosterone subsequently have normal total testosterone levels over the next 24 hours. Thus, 2 low total testosterone values are recommended to confirm the diagnosis of low testosterone.29 The NHANES do not perform second blood draws, however, we believe the strengths of the NHANES data source outweigh this weakness. Third, the NHANES does not contain data about hypogonadal symptoms it only contains serum testosterone laboratory values. However, lab values are a key component of counseling for testosterone deficiency, and reference ranges are often questioned by young men in the clinic. Additionally, because NHANES does not ask about hypogonadal symptoms, our population invariably contained some men with symptomatic, clinical hypogonadism. Thus, the normative values we provide may underestimate the testosterone values for asymptomatic men. Nevertheless, patients with hypogonadal symptoms are present within the general population and their testosterone levels are part of the physiological range of testosterone levels for all men. Fourth, the NHANES does not provide information about bioavailable or free testosterone. Bioavailable or free testosterone are unable to be calculated due to a lack of data regarding sex hormone-binding globulin in the 2011 to 2012 NHANES data. Finally, we chose to use 5-year age intervals when creating our normative values to strike a balance between longer, 10-year intervals that have been used in other testosterone studies and narrower 1-year age intervals that could be more difficult to remember. Nevertheless, if clinicians needed wider or narrower age-based values, they could be derived from NHANES using the methods we described above.
These limitations notwithstanding, our findings have important implications for clinicians, patients, payers, and policymakers. Our age-specific cutoffs for low testosterone levels can help clinicians who have struggled with diagnosing testosterone deficiency in young men. In today’s age of personalized medicine, clinicians can now use age-specific testosterone levels to evaluate young men instead of relying on a “one size fits all” approach. For patients, we offer normative reference ranges that can be used to compare their testosterone levels to age-matched peers. Our cutoffs also benefit young men who experience hypogonadal symptoms but who have historically been disqualified from treatment based on the age-independent 300 ng/dL cutoff. Patients may also receive financial benefits from these cutoffs, as many insurance companies currently do not cover testosterone therapies if a man’s testosterone is >300 ng/dL. For payers and policymakers, these age-specific cutoffs may serve as evidence-based benchmarks to guide coverage decisions for the treatment of hypogonadism. Notably, young men in their reproductive years must understand that testosterone therapy can suppress spermatogenesis and must be pursued with caution if they are interested in current or future paternity.30
CONCLUSIONS
Our findings suggest that young men have different testosterone reference ranges than older men; the management of young men should accordingly reflect these differences. In particular, providers should question the use of an age-independent cutoff for young men and should integrate age-specific cutoffs into their evaluation of young men presenting with testosterone deficiency. Future research should correlate these age-specific cutoffs to hypogonadal symptoms and responses to treatment. Development of age-specific reference ranges and cutoffs for free testosterone and sex hormone-binding globulin may also be useful in the future management of young men with hypogonadism.
